The goal of this Brief Review is to highlight literature that demonstrates how cytokines made by T lymphocytes impact the gastric epithelium, especially during Helicobacter pylori infection. These cytokines effect many of the diverse functions of the epithelium and the epithelium’s interactions with H. pylori. The focal point of this Brief Review will be on how T cell cytokines impact antimicrobial function and barrier function and how T cell cytokines influence the development and progression of cancer. Furthermore, the modulation of epithelial-derived chemokines by H. pylori infection will be discussed.

The health and function of the stomach and the intestines are essential for interacting with the external environment and with the internal microbiome through the epithelial cell layer. Specifically, the function of the stomach is to store food and provide early digestion of food by producing acid and enzymes and macerating that food with its muscular lining. There are several specialized epithelial cells that aid in the stomach performing its necessary functions. These include chief cells, enteroendocrine cells, parietal cells, stem cells, and foveolar cells (both surface mucous cells and mucous neck cells) (1) (Fig. 1). Chief cells are found in the fundic glands and, most common, deep in the glands closer to the muscularis mucosae. The digestive enzymes of the stomach, pepsins, are secreted by chief cells. Located deep in the gastric glands are the enteroendocrine cells including G cells, D cells, and enterochromaffin-like cells, which are responsible for production of gastrin, somatostatin (SOM), and histamine, respectively. Gastrin and histamine impact parietal cell and chief cell function. Gastrin stimulates enterochromaffin-like cells to release histamine and then synergistically these hormones activate parietal cells to produce hydrochloric acid and chief cells to release pepsin. Foveolar cells are simple columnar epithelial cells that line the stomach. They are also found in gastric pits and at the top of the gastric glands (necks), where they are referred to as surface mucous cells and mucous neck cells, respectively. Surface mucous cells contain large amounts of mucin at their apical surface. The mucus and bicarbonate ions produced by the foveolar cells play an important role in modulating the impact of acids on the gastric epithelium. Gastric mucous neck cells are most common in the upper region of the glands.

FIGURE 1.

Illustration of the stomach. The architecture of the human stomach is similar to the mouse with the exception of the presence of a nonglandular forestomach in the mouse. In the stomach epithelium, gastric pits lead to gastric glands that secrete gastric juice. The cellular composition of the gastric glands and pits varies based on localization in the corpus verses the antrum. Enlarged gastric pits and glands are shown containing different localization specialized epithelial cells including foveolar cells (both surface mucous cells and mucous neck cells); cells that that secrete hydrochloride acid, gastrin, SOM, and activate pepsin (parietal cells, enteroendocrine cells, and chief cells); and gastric stem cells. H. pylori colonization is denser in the antrum of the stomach than the corpus.

FIGURE 1.

Illustration of the stomach. The architecture of the human stomach is similar to the mouse with the exception of the presence of a nonglandular forestomach in the mouse. In the stomach epithelium, gastric pits lead to gastric glands that secrete gastric juice. The cellular composition of the gastric glands and pits varies based on localization in the corpus verses the antrum. Enlarged gastric pits and glands are shown containing different localization specialized epithelial cells including foveolar cells (both surface mucous cells and mucous neck cells); cells that that secrete hydrochloride acid, gastrin, SOM, and activate pepsin (parietal cells, enteroendocrine cells, and chief cells); and gastric stem cells. H. pylori colonization is denser in the antrum of the stomach than the corpus.

Close modal

The maintenance of the epithelium functions is vital for a body’s health. The gastric epithelium can be disrupted under several conditions including use of pharmacological reagents, alcohol or infection (24). Helicobacter pylori is the most common bacterial infection of the gastric mucosa. H. pylori’s prevalence is >50% of the population, but there is significant variation in the prevalence between regions of the world (5, 6). Long-term colonization by H. pylori is the most consequential risk factor for the development of gastric cancer (GC) (7), which imposes a significant global burden with over 1 million new stomach cancers diagnosed in 2018 (8). Like many bacterial pathogens, H. pylori must overcome natural defenses and the immune response to colonize and cause disease. H. pylori overcomes natural defenses of the stomach through production of urease, which neutralizes the local acidic environment, and through its flagella, which provides the ability to traverse the mucus layer and interact with epithelial cells. Other bacterial factors that aid survival of H. pylori include its adherence to the epithelium, its ability to produce of catalase to neutralize hydrogen peroxide, and its ability to acquire nutrients. Virulence factors, including the vacuolating toxin (VacA), the cytotoxin A (CagA) type 4 secretion system (T4SS), and adhesins, among others, target the epithelial cells, disrupting cell–cell communication, tight junctions, and cellular signaling of the epithelium (911). Both bacterial interactions with gastric epithelial cells (GECs) and the ongoing chronic inflammatory response to H. pylori contribute to carcinogenesis. This Brief Review will focus on how the chronic inflammatory process, especially T cell activation, impacts the epithelial cell response.

The innate immune response to H. pylori is activated through direct interactions of H. pylori or its products with the GECs. Both humoral and cellular immunity become chronically active, but this response is not effective in bacterial clearance. The cellular immune infiltrate in response to H. pylori is dominated by innate immune cells and CD4+ T cells (Fig. 2). The CD4+ T cells response is instrumental during infection in mice and humans for the development of gastritis and control of infection. T and B cell–deficient mice (RAG or SCID) do not control H. pylori colonization, nor do they exhibit inflammation like wild-type (WT) mice (12, 13). Reconstituting these immune deficient mice with CD4+ T cells results in severe gastritis, suggesting that CD4+ T cells are both necessary and sufficient for disease. MHC class II−/− mice, which lack CD4+ T cells responses, are unable to control H. pylori colonization as well as WT mice, and they do not develop a protective response to immunization (14). Using Ag-specific adoptive transfer models has confirmed the importance of the CD4+ T cell on driving gastritis through epithelial cell damage, associated proliferative and metaplastic responses. Peterson et al. (15) reconstituted SCID mice with congenic splenocytes from H. pylori–infected or naive WT mice and found significant increases in GEC apoptosis and proliferation in infected recipient and donor, compared with nonrecipient and uninfected mice at 3 mo posttransfer. These data suggest that splenocytes from H. pylori infected mice and the factors they produce contribute to GEC turnover by inducing apoptosis and proliferation.

FIGURE 2.

CD4+ T lymphocyte subsets migrate to the gastric mucosa in response to H. pylori infection and where they produce cytokines that impact epithelial cell function. In this figure, the immune cell filtrate in the lamina propria is represented. Green cells represent CD4+ T cells; blue cells represent B lymphocytes; purple cells represent dendritic cells and macrophages; and pink cells represent neutrophils. Th1 and Th17 cells dominate the response during gastritis producing IFN-γ, IL-17, IL-21, and IL-22 (possibly produced by Th22 cells). Th2 lymphocytes are not commonly activated during H. pylori infection, but when present do impact epithelial cell responses. Finally, T regulatory cells are activated during H. pylori and their presence can influence not only other T cells but also epithelial cell biology through production of IL-10 and TGF-β.

FIGURE 2.

CD4+ T lymphocyte subsets migrate to the gastric mucosa in response to H. pylori infection and where they produce cytokines that impact epithelial cell function. In this figure, the immune cell filtrate in the lamina propria is represented. Green cells represent CD4+ T cells; blue cells represent B lymphocytes; purple cells represent dendritic cells and macrophages; and pink cells represent neutrophils. Th1 and Th17 cells dominate the response during gastritis producing IFN-γ, IL-17, IL-21, and IL-22 (possibly produced by Th22 cells). Th2 lymphocytes are not commonly activated during H. pylori infection, but when present do impact epithelial cell responses. Finally, T regulatory cells are activated during H. pylori and their presence can influence not only other T cells but also epithelial cell biology through production of IL-10 and TGF-β.

Close modal

It is important to recognize the double-edged sword of a Th cell response. T cell–derived cytokines are required for activating antimicrobial responses and Ab responses against pathogens; but in contrast, there is collateral damage during chronic, exacerbated or unregulated proinflammatory responses. The balance between proinflammatory Th cells and regulatory CD4+ T cell (Tregs) cells effect H. pylori immune responses and gastric disease (1618) whereby low Treg response leads to increased inflammation and gastric disease. CD4+ T cell cytokines are often categorized by the function of the T cell that produces them (19). For example, Th1 cells produce IFN-γ; Th2 cells produce IL-4, IL-5, and IL-13; Th17 cells produce IL-17a, IL-17f, IL-21, and IL-22; Th22 cells produce IL-22; and Tregs produce IL-10 and TGF-β. Many of these cytokines can play a role in activating antimicrobial responses, wound healing, proliferation, and carcinogenesis through their signaling in epithelial cells.

Gastritis is the culmination of innate and adaptive immune response that is initiated at the intersection of H. pylori contact with GECs. H. pylori activates the gastric epithelium to produce CXCL8 (IL-8, a neutrophil chemokine), IL-6, IL-1β, GM-CSF, MCP-1 (CCL2), macrophage migration inhibitory factor (MIF), TNF-α, and TGF-β (20, 21). Many reviews have been written on the direct interaction between H. pylori and epithelial cells, so we will only briefly focus on the characteristics of H. pylori that lead to epithelial cell activation and strongly influence the T cell response.

One of the most important virulence factors of H. pylori is the CagA T4SS. It is encoded by the cag pathogenicity island (cagPAI), and this secretion system is responsible for translocating the effector protein CagA, peptidoglycan metabolites, and DNA directly into epithelial cells. The functioning of this T4SS has been shown to be vital for carcinogenesis and has been referred to as an oncogenic factor. The biosynthesis of heptose-1,7-bisphosphate (HBP), an intermediate metabolite of LPS, contributes to cagPAI-dependent activation of epithelial cells (22). OipA is a phase-variable outer membrane protein that is postulated to bind to an integrin (23). Experimental analysis of phase on/off mutants of H. pylori demonstrate that OipA is necessary but not sufficient for CagA translocation into host epithelial cells (24). The significance of the T4SS dependent activation of epithelial cells is activation of proinflammatory signaling that induces the transcriptional activation and secretion of chemokines such as CXCL8 (IL-8), which recruits neutrophils to the site of infection. Polarization of the Th cell response is influenced in H. pylori–infected humans by both whether the patient is infected with a CagA-positive strain and their stage of progression to gastric carcinogenesis (25). Patients colonized with CagA+ strains had Th1-mediated cellular immunity in earlier stages of gastric carcinogenesis. Patients colonized with CagA+ strains in advanced stages were dominated by Th2-mediated humoral immunity and negatively associated with a large number of Tregs.

Several soluble or secreted proteins of H. pylori also directly impact the function of GECs and APC. VacA, a pore-forming toxin, induces mitochondrial damage and contributes to epithelial cell death through apoptosis and programmed necrosis (26, 27). Large amounts of urease produced by H. pylori to accommodate its survival in the stomach’s acidic environment induce production of IL-6 and TNF-α in primary GECs and in the human GEC line MKN-45 (20). In addition, urease has been shown to contribute to apoptosis and inflammation through its interaction with host cells. The interaction of urease with CD74 on host cells contributes to CXCL8 production by GECs (28), whereas urease binding to MHC class II contributes to apoptosis of GECs (29). These are relevant findings because they impact Ag uptake by recruited phagocytes and expression of T cell skewing cytokines.

The epithelial cell layer is intended to be a major defensive part of the innate immune response setting off alarms through TLR and other pattern recognition receptors. Disruption of the epithelial cell barrier by virulence factors leads to the innate activation of the immune response (reviewed in Ref. 23) and trigger innate activation of APCs (30, 31). For example, high temperature regulator A (HtrA) disrupts epithelial barrier through cleavage of the ectodomain of E-cadherin (32, 33), permitting H. pylori, outer membrane vesicles, and H. pylori soluble factors to invade spaces between GECs (34).

As an extracellular bacterium that produces several secreted factors, H. pylori activates a strong CD4+ T cell response (31, 35). Activation, proliferation, and differentiation of CD4+ T cells requires several signals (3539). The first and second signals are mediated through the T cell’s receptor with its cognate peptide-loaded MHC molecule on the APC (40) and through costimulatory molecule interactions between the T cell–expressed CD28 molecule and B7.1 or B7.2 molecules on the APC (41). These two signals result in activation, clonal expansion and proliferation of the T cells. A third signal is required for T cell differentiation and is provided by the cytokine microenvironment (42). Although it is widely accepted that H. pylori does not activate APCs as strongly as other gastrointestinal pathogens, APC produce several T cell differentiating cytokines including (but not limited to) IL-1β, IL-10, IL-12, IL-18, IL-23, and TGF-β in response to H. pylori (4345). These cytokines are induced through pattern recognition receptors and inflammasome activation (4648) triggering differentiation of Th1 and Th17 responses. Interestingly, it has been demonstrated that H. pylori factors including VacA and γ-glutamyl transpeptidase (GGT) downregulate the magnitude of the proinflammatory T cell response. Specifically, GGT converts glutamine into glutamate and ammonia and converts glutathione into glutamate and cysteinylglycine (reviewed in Ref. 49). H. pylori GGT induces immune tolerance through the inhibition of T cell–mediated immunity and APC cytokine production. VacA impacts several cell types as a pore-forming toxin. It can directly inhibit T cell proliferation and IL-2 production but also indirectly impacts T cell differentiation to targeting myeloid cells especially in young mouse models to induce tolerance (reviewed in Ref. 50) VacA and GGT similarly impact dendritic cell activity (promoting Treg differentiation) and inhibit T cell proliferation.

IFN-γ–producing CD4+ T cells, Th1 cells, are activated during H. pylori infection. Increased presence of Th1 cells (increased IFN-γ) are associated with more detrimental outcomes of H. pylori infection (51, 52). IFN-γ acts synergistically with TNF-α to activate macrophages and NK cells, but most mucosal epithelial cells also express the IFN-γR at the basolateral membrane (53). IFN-γ signals activation and nuclear translocation of STAT1. IFN-γ induces several chemokines that regulate mucosal T cell trafficking. These CXC chemokines, CXCL9, CXCL10, and CXCL11, specifically attract CXCR3+CD4+ T cells. IFN-γ and TNF-α strongly induced secretion of these chemokines in GECs (Kato III, NCI, and AGS cells) (54). Interestingly, in some settings H. pylori may inhibit STAT1 activation by IFN-γ (55), and soluble or membrane fractions of H. pylori have been shown to prevent the chemokine expression in the above mentioned GECs (54). Conversely, in another study, cagPAI+H. pylori strains augmented GEC responses to IFN-γ and specifically increased CXCL9, CXCL10, and CXCL11 expression (56). Other chemokines are also induced by H. pylori and IFN-γ. The murine GEC line, GSM06, responded synergistically to H. pylori and IFN-γ to induce CXCL2 and inducible NO synthase expression, supporting inflammation (57). Results from H. pylori infection of IFN-γ−/− mice suggest that IFN-γ plays a primary role in driving inflammation, with minimal effect on colonization levels (58).

The turnover of mucosal epithelial cells is vital for homeostasis when the epithelial cell layer is colonized with inflammation-inducing bacterial colonizers or virulent bacterium. Homeostasis is maintained through a process of apoptosis balanced with proliferation. Inflammation and cytokines can disrupt this balance. Specifically, IFN-γ enhances apoptosis during H. pylori infection. This has been demonstrated in organoid cultures (53) and in cell culture assays with human GECs (AGS cells and Kato III cells) (59). Mechanistically, IFN-γ directly enhances caspase 3 activation and indirectly induces increased expression of MHC class II molecules on the surface of GECs to which H. pylori can bind and trigger apoptosis through Bax activation. IFN-γ clearly has a proapoptotic role on GECs, but it is also vital for enhancing gastritis through activation of chemotactic gradients, which enhance immune cell infiltration to the gastric mucosa.

There is also evidence that IFN-γ can alter the lineage and, therefore, the function of GECs. The human GEC line, NCI-N87, increased it expression of mucus, mucin 6 (Muc6), trefoil factor 2 (Tff2), and pepsinogen II in response to IFN-γ, suggesting NCI-N87 cells became more like a mucous neck cell with this treatment (60). Infusion of IFN-γ (in mice) expanded the mucous neck cell compartment and led to the proliferation of a gastric progenitor cell in the antral gland, which can give rise to all gastric lineages in those glands (61). These were key experiments for understanding connections between inflammation and carcinogenesis.

The Th17 subset also contributes to the immunopathogenic response to H. pylori. Th17 cells are differentiated in the presence of IL-1β, IL-6, and TGF-β; the subset is transcriptionally stabilized and expanded in the presence of IL-23 and IL-21. Once differentiated, Th17 cells make several cytokines, including IL-17a, IL-17f, IL-21, and IL-22.

IL-17a is the cytokine that has the greatest affinity for IL-17RA/RC on epithelial cells, and its canonical activation of the IL-17R leads to activation of several transcription factors including NF-κB, AP-1, and C/EBP (62). The major consequence of IL-17 signaling is induction of a chemotactic response recruiting PMNs (through activation of CXCL1, CXCL2, CCL2, and CCL5). This tight association between IL-17A expression and CXCL8 induction by epithelial cells has been investigated in H. pylori–infected patients. Increased levels of IL-17A and CXCL8 are reported during H. pylori infection compared with uninfected patients (63, 64). Moreover, expression of IL-17A and CXCL8 correlates with PMN infiltration in the H. pylori–infected patients. Furthermore, it has been demonstrated that isolated lamina propria mononuclear cells from H. pylori–infected patients can induce the production of CXCL8 in an IL-17A–dependent fashion; inhibition of IL-17 using an anti–IL-17A Ab led to decreased CXCL8 expression (63). Interestingly, IL-17 alone is not a strong inducer of NF-κB, but its synergistic response with IFN-γ, lymphotoxin, and TNF-α leads to a strong cellular response (65). In the case of costimulation with TNF-α, IL-17 signaling leads to increases in mRNA stability of IL-17 target genes (66, 67).

Central to regulation of IL-17 signaling is the Act1 protein and several TNF receptor–associated factors (TRAFs). Act1, a U-box E3 ubiquitin ligase, is recruited to the IL-17R [and ubiquitinates TRAF6 (68)]. These events are critical for NF-κB activation, but not required for the mRNA stability processes mediated by IL-17 signaling (67). In contrast, TRAF4 competes for the same binding site on Act1 as TRAF6. Although TRAF4 restricts the level of NF-κB activation as a result of IL-17 signaling (69), it can also activate signaling in a MEKK3 dependent pathway. TRAF4-mediated signaling has been studied extensively in keratinocytes (70), and although the importance of these signaling events in GECs is yet to be determined, they may have implications in ulcer-healing or carcinogenesis. In keratinocytes, TRAF4 can also mediate MEKK3-dependent ERK 5 activation inducing Steap4, which is critical for cellular metabolism and proliferation (70). Moreover, TRAF4 can also transactivate the epidermal growth factor receptor (EGFR). Chen et al. (71) demonstrate that Act1–TRAF4–ERK5 signaling is a result of IL-17a–induced EGFR transactivation and critical for stimulating epidermal hyperplasia and tumor growth in keratinocytes. Another regulator, TRAF3, interferes with Act1 binding to IL-17R, providing a proximal regulation of IL-17 signaling (72). TRAF3 is also regulated by Nuclear Dbf2‐related kinase 1 (NDR1). NDR1 can bind to TRAF3 preventing it from binding to IL-17R, which allows for the formation of the IL-17R–Act1–TRAF6- signaling complex formation and canonical activation of IL-17 signaling.

IL-17a and IL-22 act synergistically to activate antimicrobial responses in epithelial cells (reviewed in Ref. 73). It is difficult to separate the importance of Th17-mediated induction of neutrophil recruitment from the importance of activation of antimicrobial proteins. Nevertheless, there is a clear trend toward the need for a Th17 response to control H. pylori; both PMNs and antimicrobial proteins production are likely contributing factors. IL-17a and IL-22 together enhanced the ability of GECs to upregulate expression of calprotectin, lipocalin and some β-defensins (74). Furthermore, activating GECs with IL-17a and IL-22 increased their ability to kill H. pylori in vitro compared with treatment with each cytokine alone (74).

IL-17f also signals through the IL-17RA/RC complex, but research on mechanisms by which IL-17f acts on GECs or in the tissue during H. pylori infection is minimal. Because IL-17a appears to be the predominately produced cytokine compared with IL-17f during H. pylori infection (75), an effect of IL-17f may be minimal and/or some IL-17R signaling may be redundant. Several studies have investigated whether polymorphism in the IL-17f gene are linked to GC, but there is no consistency in their findings (76). Still, there is no profound understanding of expression of these receptors on GEC subsets and regulation of these receptors by inflammatory stimuli.

IL-22 is another T cell–derived cytokine that can activate antimicrobial and inflammatory epithelial cell functions, especially in the context of H. pylori infection (77). Although we have placed the IL-22 under the Th17 cytokine umbrella for this Brief Review, this cytokine may also be produced by Th22 cells. In fact, during H. pylori infection, whereas IL-22 expression has been reported, it is not clear if the cells producing the cytokine are Th17 or Th22 cells. IL-22 signals through a heterodimeric receptor of IL-22RA1 and IL-10Rβ. Because IL-10Rβ is constitutively expressed, regulation of IL-22 signaling begins with regulated expression of IL-22RA1. IL-22 activates STAT3 signaling and enhances gene transcription of select genes involved in antimicrobial activity. Increased expression of IL-22 is reported in H. pylori–infected mice and humans (74, 77), and its expression correlates with the level of H. pylori colonization and level of gastritis (77). Remarkably, GECs upregulated the IL-22RA1 in response to H. pylori in a CagA-dependent manner (77). The influence of IL-22 on GEC is not clear cut. In one report, IL-22 downregulated CCL20 expression of H. pylori–induced AGS cells, suggesting IL-22 may play a role protecting the gastric mucosa from damage induced by inflammation (78). In contrast, IL-22−/− mice have reduced expression of CXCL2 in response to H. pylori infection compared with WT BALB/c mice (77). This reduced CXCL2 expression correlates with reduced influx of myeloid-derived suppressor cells, reduced expression of calprotectin, and increased Th1 responses (77), suggesting a proinflammatory role for IL-22 in this mouse model.

IL-22 has also been shown to induce expression of matrix metalloproteinase-10 (MMP-10) in GECs activating host defense pathways (79). MMP-10 expression is increased in parietal cells and chief cells in the H. pylori–infected gastric mucosa, and IL-22 (not IL-17a or IFN-γ) enhanced H. pylori’s activation of MMP-10 expression in AGS cells in an ERK dependent pathway (79). MMP-10 activates GECs and H. pylori–induced inflammation. MMP-10−/− mice as well as MMP-10−/−/IL-22−/− mice have reduced gastritis associated with decreased expression of CXCL16 and reduced CD8+ T cell migration (79). Interestingly, the authors of this study also found that Reg3a, ZO-1, and occludin expression was inhibited by MMP-10, and they hypothesize that MMP-10 may facilitate persistence and damage to the epithelial cell layer through these pathways (79). Overall, these studies suggest that IL-22–dependent GEC activation contributes to regulating the gastritis response to H. pylori.

Th2 cells are typically thought of as the CD4+ T cells that produce IL-4, IL-5, and IL-13 with the goal of helping to activate the humoral response and mast cells. Binding of IL-4 or of IL-13 initiates Jak-dependent tyrosine phosphorylation of the IL-4Rα-chain and STAT6. Activation of STAT6 in GECs is required for the gastrointestinal response to nematode infections or parasites (80). Th2 responses are not strongly activated during H. pylori infection, relative to Th1 or Th17 responses in humans, rhesus macaques, gerbils, or mice (8185), but the cytokines produced by Th2 cells may indirectly downregulate gastritis. In fact, even though C57BL/6 WT mice do not demonstrate an increase in IL-4 expression in response to H. pylori infection, IL-4−/− mice do exhibit an increase in IFN-γ expression and increased gastritis (82). Therefore, understanding how IL-4 might regulate IFN-γ responses may increase our understanding of how these cytokines inhibit or activate GEC responses. During chronic gastritis, atrophy of gastric glands has been reported resulting in a decrease in the number of D cells (SOM-secreting cells) and an increase in the number of G cells (gastrin-secreting cells) (86, 87). The balance of Th1 and Th2 cytokines, specifically IFN-γ and IL-4, may influence the turnover and function of these neuroendocrine cell populations in the gastric mucosa of chronic Helicobacter infection; IL-4 provides a stimulus for SOM release from D cells and, therefore, provides protection from Th1 mediated inflammation in the H. felis model (88).

IL-13 is also produced by Th2 cells, but there are little data on the direct role of IL-13 in GEC function. The IL-13R has been detected on chief cells and in models of induced spasmolytic polypeptide-expressing metaplasia. IL-13 was shown to be necessary and sufficient for chief cell transdifferentiation into metaplasia following parietal cell loss (89). In a small study of 23 H. pylori–positive subjects, IL-13 localized to the inflammatory infiltrate (90). More specifically, in cases where the patients had intestinal metaplasia or intestinal type GC, IL-13 also localized to the GECs (90). The impact of IL-13 on intestinal epithelial cells has been studied, but its impact on GECs is largely undescribed in the literature.

The presence of Tregs reduces the pathological outcomes of H. pylori infection in mice and human (9195). Generally, the presence of Tregs is correlated with reduced gastritis, but at the expense of greater levels of H. pylori colonization. Mouse models demonstrate that depletion of Tregs leads to increased levels of IFN-γ and increased inflammation (96). Tregs may be recruited to the H. pylori colonized mucosa via CCL20/CCR6-mediated chemotaxis orchestrated by the GEC response. CCL20 is upregulated in gastric biopsies of H. pylori–infected patients (97), and further, CCL20 induction in GECs is cagPAI dependent. CCL20 expression was shown to induce Treg migration; for instance, CD4+Foxp3+ T cells (Tregs) isolated from H. pylori–infected patients migrated to rCCL20 in vitro whereas CD4+Foxp3 T cells did not (97).

Tregs are defined by their ability to regulate proinflammatory T cell responses through direct activation of apoptosis, through secretion of inhibitory cytokines, or by depleting the microenvironment of extracellular ATP and IL-2 (98, 99). Tregs not only target T cells but also may target GECs through production of IL-10 and TGF-β. Although IL-10 expression may be protective during inflammation, once cancer develops, IL-10 may be detrimental. In fact, increased IL-10 in the serum is an unfavorable prognostic marker for GC (100). IL-10 in the tumor microenvironment may be produced by a number of cell types. One potential mechanism by which IL-10 could stimulate GECs in the tumor is through activating c-Met–STAT3. GEC lines responded to culture supernatant cancer-associated macrophages in an IL-10–dependent way to induce proliferation and migration, whereas it also suppressed apoptosis (101).

TGF-β is also produced by Tregs (and other immune cells) and may act as a tumor suppressor in early stages but a tumor promoter in later stages (102). TGF-β signals through many cell types, including fibroblasts and mesothelial cells, inducing extracellular matrix protein synthesis and contributing to fibrogenesis (103). TGF-β1 and TGF-β2 bind to TGF-βR I through TGF-βRII to activate its serine/threonine kinase. The activated dimeric receptor then activates a complex of Smad proteins, which facilitates transcription of target genes (104). To investigate the role of TGF-β signaling during H. pylori infection, mice that overexpress the dominant negative mutant of the TGF-β RII in their stomach were generated (pS2-dnRII) (105). When these mice and WT littermates were infected with H. pylori, the mice lacking TGF-β signaling developed gastric adenocarcinoma with high cell proliferation index in their epithelial cells compared with their WT littermates, suggesting TGF-β provides a protective effect suppressing carcinogenesis (105). In vitro studies performed on GEC lines (BGC823 and MKN-45) demonstrated that TGF-β treatment downregulated expression of E-cadherin significantly, whereas it upregulated expression of epithelial mesenchymal transition-related proteins, snail and vimentin (106); interestingly, upstream of TGF-β signaling, MFAP2 is activated and promotes this activity. Increased levels of TGF-β in the serum and gastric tissue are associated with advanced cancer (107109), and expression appears to be higher in the tissues of intestinal type GC than diffuse type GC (110). Tumor growth may be promoted by TGF-β by inducing epithelial cells to undergo epithelial-mesenchymal transition through upregulating long noncoding RNA urothelial carcinoma associated 1 (LncRNA UCA1), which when silenced in GC cell lines reduced the levels of snail and vimentin and promoted expression of E-cadherin and ZO-1 (111). Moreover, erythrocyte membrane protein band 4.1-like 5 is also a target of TGF-β signaling and regulates GC cell metastasis (112). So, although Tregs may play a role downregulating the inflammatory response to H. pylori, Tregs may be detrimental during GC because Tregs and their cytokines activate procarcinogenic pathways in the tumor microenvironment.

The inflammatory response to H. pylori significantly influences the outcome of infection, and although this response involves the innate and the adaptive immune response, T lymphocytes play a major role in orchestrating the gastritis. CD4+ T cell–derived cytokines amplify the innate response by recruiting PMNs and macrophages to the site of infection, but they can also directly impact epithelial cell biology and carcinogenesis. Our understanding of how many of the T cell–derived cytokines impact GEC functions has increased in the last decade, but there are many gaps in knowledge to address. We lack understanding of the temporal activation of the epithelial cell response. Proinflammatory responses are necessary for control of the bacterial colonization but chronically can lead to carcinogenesis; however, sustaining proinflammatory responses may allow for antitumor responses and a favorable prognosis. Second, many studies that have investigated the GEC response to H. pylori and/or T cell–derived cytokines have been performed in a reductionist manner when, in fact, there appears to be significant cross-regulation of epithelial cell responses by cytokines. Furthermore, there is evidence that increased numbers and mislocalized stem cell presence in gastric pits is associated with carcinogenesis. The links between inflammation and T cell–derived cytokines in the gastric tissue has largely been unexplored. Finally, the increased use of gastroids is vital for our increased understanding of the consequence of expression and signaling of these cytokines and H. pylori on the specialized cells of the gastric mucosa. Gastroids combined with single cell analyses will inform which cells respond to the stimuli and how. Research in this area will help identify appropriate promising therapeutic targets for persons with detrimental outcomes of H. pylori infection from chronic gastritis to the different types of GC.

I acknowledge the work of my Research Specialist, Beverly R.E.A. Dixon, M.S., for continued support of the research program and for contributions in editing this Brief Review.

This work was supported by Office of Medical Research, Veterans Affairs Merit Review Grant IBX000915A (to H.M.S.A.). The content is solely the responsibility of the author and does not necessarily represent the official views of the Department of Veterans Affairs.

Abbreviations used in this article:

CagA

cytotoxin A

cagPAI

cag pathogenicity island

GC

gastric cancer

GEC

gastric epithelial cell

GGT

γ-glutamyl transpeptidase

MMP-10

matrix metalloproteinase-10

SOM

somatostatin

TRAF

TNF receptor–associated factor

Treg

regulatory CD4+ T cell

T4SS

type 4 secretion system

VacA

vacuolating toxin

WT

wild-type.

1
Gordon Betts
,
J.
,
P.
Desaix
,
E. W.
Johnson
,
J. E.
Johnson
,
O.
Korol
,
D.
Kruse
,
B.
Poe
,
J.
Wise
,
M. D.
Womble
,
K. A.
Young
;
OpenStax College
.
2016
.
The digestive system
. In
Anatomy & Physiology.
OpenStax College, Rice University
,
Houston, TX
.
2
Fromm
,
D.
1987
.
How do non-steroidal anti-inflammatory drugs affect gastric mucosal defenses?
Clin. Invest. Med.
10
:
251
258
.
3
Loguercio
,
C.
,
C.
Tuccillo
,
A.
Federico
,
V.
Fogliano
,
C.
Del Vecchio Blanco
,
M.
Romano
.
2009
.
Alcoholic beverages and gastric epithelial cell viability: effect on oxidative stress-induced damage.
J. Physiol. Pharmacol.
60
(
Suppl. 7
):
87
92
.
4
Wroblewski
,
L. E.
,
R. M.
Peek
Jr
.
2011
.
“Targeted disruption of the epithelial-barrier by Helicobacter pylori”.
Cell Commun. Signal.
9
:
29
.
5
Kotilea
,
K.
,
P.
Bontems
,
E.
Touati
.
2019
.
Epidemiology, diagnosis and risk factors of Helicobacter pylori infection.
Adv. Exp. Med. Biol.
1149
:
17
33
.
6
Hooi
,
J. K. Y.
,
W. Y.
Lai
,
W. K.
Ng
,
M. M. Y.
Suen
,
F. E.
Underwood
,
D.
Tanyingoh
,
P.
Malfertheiner
,
D. Y.
Graham
,
V. W. S.
Wong
,
J. C. Y.
Wu
, et al
.
2017
.
Global prevalence of Helicobacter pylori infection: systematic review and meta-analysis.
Gastroenterology
153
:
420
429
.
7
Kato
,
S.
,
N.
Matsukura
,
K.
Tsukada
,
N.
Matsuda
,
T.
Mizoshita
,
T.
Tsukamoto
,
M.
Tatematsu
,
Y.
Sugisaki
,
Z.
Naito
,
T.
Tajiri
.
2007
.
Helicobacter pylori infection-negative gastric cancer in Japanese hospital patients: incidence and pathological characteristics.
Cancer Sci.
98
:
790
794
.
8
Bray
,
F.
,
J.
Ferlay
,
I.
Soerjomataram
,
R. L.
Siegel
,
L. A.
Torre
,
A.
Jemal
.
2018
.
Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
CA Cancer J. Clin.
68
:
394
424
.
9
Chmiela
,
M.
,
J.
Kupcinskas
.
2019
.
Review: pathogenesis of Helicobacter pylori infection.
Helicobacter
24
(
S1
Suppl. 1
): e12638.
10
Alzahrani
,
S.
,
T. T.
Lina
,
J.
Gonzalez
,
I. V.
Pinchuk
,
E. J.
Beswick
,
V. E.
Reyes
.
2014
.
Effect of Helicobacter pylori on gastric epithelial cells.
World J. Gastroenterol.
20
:
12767
12780
.
11
Javed
,
S.
,
E. C.
Skoog
,
J. V.
Solnick
.
2019
.
Impact of Helicobacter pylori virulence factors on the host immune response and gastric pathology.
Curr. Top. Microbiol. Immunol.
421
:
21
52
.
12
Gray
,
B. M.
,
C. A.
Fontaine
,
S. A.
Poe
,
K. A.
Eaton
.
2013
.
Complex T cell interactions contribute to Helicobacter pylori gastritis in mice.
Infect. Immun.
81
:
740
752
.
13
Eaton
,
K. A.
,
S. R.
Ringler
,
S. J.
Danon
.
1999
.
Murine splenocytes induce severe gastritis and delayed-type hypersensitivity and suppress bacterial colonization in Helicobacter pylori-infected SCID mice.
Infect. Immun.
67
:
4594
4602
.
14
Pappo
,
J.
,
D.
Torrey
,
L.
Castriotta
,
A.
Savinainen
,
Z.
Kabok
,
A.
Ibraghimov
.
1999
.
Helicobacter pylori infection in immunized mice lacking major histocompatibility complex class I and class II functions.
Infect. Immun.
67
:
337
341
.
15
Peterson
,
R. A.
 II
,
T.
Hoepf
,
K. A.
Eaton
.
2003
.
Adoptive transfer of splenocytes in SCID mice implicates CD4+ T cells in apoptosis and epithelial proliferation associated with Helicobacter pylori-induced gastritis.
Comp. Med.
53
:
498
509
.
16
Serrano
,
C.
,
S. W.
Wright
,
D.
Bimczok
,
C. L.
Shaffer
,
T. L.
Cover
,
A.
Venegas
,
M. G.
Salazar
,
L. E.
Smythies
,
P. R.
Harris
,
P. D.
Smith
.
2013
.
Downregulated Th17 responses are associated with reduced gastritis in Helicobacter pylori-infected children.
Mucosal Immunol.
6
:
950
959
.
17
Jafarzadeh
,
A.
,
T.
Larussa
,
M.
Nemati
,
S.
Jalapour
.
2018
.
T cell subsets play an important role in the determination of the clinical outcome of Helicobacter pylori infection.
Microb. Pathog.
116
:
227
236
.
18
Bagheri
,
N.
,
L.
Salimzadeh
,
H.
Shirzad
.
2018
.
The role of T helper 1-cell response in Helicobacter pylori-infection.
Microb. Pathog.
123
:
1
8
.
19
Raphael
,
I.
,
S.
Nalawade
,
T. N.
Eagar
,
T. G.
Forsthuber
.
2015
.
T cell subsets and their signature cytokines in autoimmune and inflammatory diseases.
Cytokine
74
:
5
17
.
20
Tanahashi
,
T.
,
M.
Kita
,
T.
Kodama
,
Y.
Yamaoka
,
N.
Sawai
,
T.
Ohno
,
S.
Mitsufuji
,
Y. P.
Wei
,
K.
Kashima
,
J.
Imanishi
.
2000
.
Cytokine expression and production by purified Helicobacter pylori urease in human gastric epithelial cells.
Infect. Immun.
68
:
664
671
.
21
Beswick
,
E. J.
,
I. V.
Pinchuk
,
G.
Suarez
,
J. C.
Sierra
,
V. E.
Reyes
.
2006
.
Helicobacter pylori CagA-dependent macrophage migration inhibitory factor produced by gastric epithelial cells binds to CD74 and stimulates procarcinogenic events.
J. Immunol.
176
:
6794
6801
.
22
Stein
,
S. C.
,
E.
Faber
,
S. H.
Bats
,
T.
Murillo
,
Y.
Speidel
,
N.
Coombs
,
C.
Josenhans
.
2017
.
Helicobacter pylori modulates host cell responses by CagT4SS-dependent translocation of an intermediate metabolite of LPS inner core heptose biosynthesis.
PLoS Pathog.
13
: e1006514.
23
Posselt
,
G.
,
S.
Backert
,
S.
Wessler
.
2013
.
The functional interplay of Helicobacter pylori factors with gastric epithelial cells induces a multi-step process in pathogenesis.
Cell Commun. Signal.
11
:
77
.
24
Horridge
,
D. N.
,
A. A.
Begley
,
J.
Kim
,
N.
Aravindan
,
K.
Fan
,
M. H.
Forsyth
.
2017
.
Outer inflammatory protein a (OipA) of Helicobacter pylori is regulated by host cell contact and mediates CagA translocation and interleukin-8 response only in the presence of a functional cag pathogenicity island type IV secretion system.
Pathog. Dis.
DOI: 10.1093/femspd/ftx113.
25
Wang
,
S. K.
,
H. F.
Zhu
,
B. S.
He
,
Z. Y.
Zhang
,
Z. T.
Chen
,
Z. Z.
Wang
,
G. L.
Wu
.
2007
.
CagA+ H pylori infection is associated with polarization of T helper cell immune responses in gastric carcinogenesis.
World J. Gastroenterol.
13
:
2923
2931
.
26
Yamasaki
,
E.
,
A.
Wada
,
A.
Kumatori
,
I.
Nakagawa
,
J.
Funao
,
M.
Nakayama
,
J.
Hisatsune
,
M.
Kimura
,
J.
Moss
,
T.
Hirayama
.
2006
.
Helicobacter pylori vacuolating cytotoxin induces activation of the proapoptotic proteins Bax and Bak, leading to cytochrome c release and cell death, independent of vacuolation.
J. Biol. Chem.
281
:
11250
11259
.
27
Radin
,
J. N.
,
C.
González-Rivera
,
S. E.
Ivie
,
M. S.
McClain
,
T. L.
Cover
.
2011
.
Helicobacter pylori VacA induces programmed necrosis in gastric epithelial cells.
Infect. Immun.
79
:
2535
2543
.
28
Beswick
,
E. J.
,
I. V.
Pinchuk
,
K.
Minch
,
G.
Suarez
,
J. C.
Sierra
,
Y.
Yamaoka
,
V. E.
Reyes
.
2006
.
The Helicobacter pylori urease B subunit binds to CD74 on gastric epithelial cells and induces NF-kappaB activation and interleukin-8 production.
Infect. Immun.
74
:
1148
1155
.
29
Fan
,
X.
,
H.
Gunasena
,
Z.
Cheng
,
R.
Espejo
,
S. E.
Crowe
,
P. B.
Ernst
,
V. E.
Reyes
.
2000
.
Helicobacter pylori urease binds to class II MHC on gastric epithelial cells and induces their apoptosis.
J. Immunol.
165
:
1918
1924
.
30
Krauss-Etschmann
,
S.
,
R.
Gruber
,
K.
Plikat
,
I.
Antoni
,
H.
Demmelmair
,
D.
Reinhardt
,
S.
Koletzko
.
2005
.
Increase of antigen-presenting cells in the gastric mucosa of Helicobacter pylori-infected children.
Helicobacter
10
:
214
222
.
31
Suzuki
,
T.
,
K.
Kato
,
S.
Ohara
,
K.
Noguchi
,
H.
Sekine
,
H.
Nagura
,
T.
Shimosegawa
.
2002
.
Localization of antigen-presenting cells in Helicobacter pylori-infected gastric mucosa.
Pathol. Int.
52
:
265
271
.
32
Löwer
,
M.
,
C.
Weydig
,
D.
Metzler
,
A.
Reuter
,
A.
Starzinski-Powitz
,
S.
Wessler
,
G.
Schneider
.
2008
.
Prediction of extracellular proteases of the human pathogen Helicobacter pylori reveals proteolytic activity of the Hp1018/19 protein HtrA.
PLoS One
3
: e3510.
33
Hoy
,
B.
,
M.
Löwer
,
C.
Weydig
,
G.
Carra
,
N.
Tegtmeyer
,
T.
Geppert
,
P.
Schröder
,
N.
Sewald
,
S.
Backert
,
G.
Schneider
,
S.
Wessler
.
2010
.
Helicobacter pylori HtrA is a new secreted virulence factor that cleaves E-cadherin to disrupt intercellular adhesion.
EMBO Rep.
11
:
798
804
.
34
Chmiela
,
M.
,
N.
Walczak
,
K.
Rudnicka
.
2018
.
Helicobacter pylori outer membrane vesicles involvement in the infection development and Helicobacter pylori-related diseases.
J. Biomed. Sci.
25
:
78
.
35
Algood
,
H. M.
,
J.
Gallo-Romero
,
K. T.
Wilson
,
R. M.
Peek
Jr.
,
T. L.
Cover
.
2007
.
Host response to Helicobacter pylori infection before initiation of the adaptive immune response.
FEMS Immunol. Med. Microbiol.
51
:
577
586
.
36
Odenbreit
,
S.
,
J.
Püls
,
B.
Sedlmaier
,
E.
Gerland
,
W.
Fischer
,
R.
Haas
.
2000
.
Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion.
Science
287
:
1497
1500
.
37
Oertli
,
M.
,
M.
Sundquist
,
I.
Hitzler
,
D. B.
Engler
,
I. C.
Arnold
,
S.
Reuter
,
J.
Maxeiner
,
M.
Hansson
,
C.
Taube
,
M.
Quiding-Järbrink
,
A.
Müller
.
2012
.
DC-derived IL-18 drives Treg differentiation, murine Helicobacter pylori-specific immune tolerance, and asthma protection.
J. Clin. Invest.
122
:
1082
1096
.
38
Kranzer
,
K.
,
L.
Söllner
,
M.
Aigner
,
N.
Lehn
,
L.
Deml
,
M.
Rehli
,
W.
Schneider-Brachert
.
2005
.
Impact of Helicobacter pylori virulence factors and compounds on activation and maturation of human dendritic cells.
Infect. Immun.
73
:
4180
4189
.
39
Niess
,
J. H.
,
S.
Brand
,
X.
Gu
,
L.
Landsman
,
S.
Jung
,
B. A.
McCormick
,
J. M.
Vyas
,
M.
Boes
,
H. L.
Ploegh
,
J. G.
Fox
, et al
.
2005
.
CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance.
Science
307
:
254
258
.
40
Burgdorf
,
S.
,
C.
Kurts
.
2008
.
Endocytosis mechanisms and the cell biology of antigen presentation.
Curr. Opin. Immunol.
20
:
89
95
.
41
Rudd
,
C. E.
,
A.
Taylor
,
H.
Schneider
.
2009
.
CD28 and CTLA-4 coreceptor expression and signal transduction.
Immunol. Rev.
229
:
12
26
.
42
Curtsinger
,
J. M.
,
M. F.
Mescher
.
2010
.
Inflammatory cytokines as a third signal for T cell activation.
Curr. Opin. Immunol.
22
:
333
340
.
43
Guiney
,
D. G.
,
P.
Hasegawa
,
S. P.
Cole
.
2003
.
Helicobacter pylori preferentially induces interleukin 12 (IL-12) rather than IL-6 or IL-10 in human dendritic cells.
Infect. Immun.
71
:
4163
4166
.
44
Hafsi
,
N.
,
P.
Voland
,
S.
Schwendy
,
R.
Rad
,
W.
Reindl
,
M.
Gerhard
,
C.
Prinz
.
2004
.
Human dendritic cells respond to Helicobacter pylori, promoting NK cell and Th1-effector responses in vitro.
J. Immunol.
173
:
1249
1257
.
45
Yasmin
,
S.
,
B.
Dixon
,
D.
Olivares-Villagomez
,
H. M. S.
Algood
.
2019
.
Interleukin-21 (IL-21) downregulates dendritic cell cytokine responses to Helicobacter pylori and modulates T lymphocyte IL-17A expression in Peyer’s patches during infection.
Infect. Immun.
DOI: 10.1128/IAI.00237-19.
46
Pachathundikandi
,
S. K.
,
J.
Lind
,
N.
Tegtmeyer
,
E. M.
El-Omar
,
S.
Backert
.
2015
.
Interplay of the gastric pathogen Helicobacter pylori with toll-like receptors.
BioMed Res. Int.
2015
: 192420.
47
Li
,
X.
,
S.
Liu
,
J.
Luo
,
A.
Liu
,
S.
Tang
,
S.
Liu
,
M.
Yu
,
Y.
Zhang
.
2015
.
Helicobacter pylori induces IL-1β and IL-18 production in human monocytic cell line through activation of NLRP3 inflammasome via ROS signaling pathway.
Pathog. Dis.
DOI: 10.1093/femspd/ftu024.
48
Semper
,
R. P.
,
R.
Mejías-Luque
,
C.
Groß
,
F.
Anderl
,
A.
Müller
,
M.
Vieth
,
D. H.
Busch
,
C.
Prazeres da Costa
,
J.
Ruland
,
O.
Groß
,
M.
Gerhard
.
2014
.
Helicobacter pylori-induced IL-1β secretion in innate immune cells is regulated by the NLRP3 inflammasome and requires the cag pathogenicity island.
J. Immunol.
193
:
3566
3576
.
49
Ricci
,
V.
,
M.
Giannouli
,
M.
Romano
,
R.
Zarrilli
.
2014
.
Helicobacter pylori gamma-glutamyl transpeptidase and its pathogenic role.
World J. Gastroenterol.
20
:
630
638
.
50
Djekic
,
A.
,
A.
Müller
.
2016
.
The immunomodulator VacA promotes immune tolerance and persistent Helicobacter pylori infection through its activities on T-cells and antigen-presenting cells.
Toxins (Basel)
DOI: 10.3390/toxins8060187.
51
Bamford
,
K. B.
,
X.
Fan
,
S. E.
Crowe
,
J. F.
Leary
,
W. K.
Gourley
,
G. K.
Luthra
,
E. G.
Brooks
,
D. Y.
Graham
,
V. E.
Reyes
,
P. B.
Ernst
.
1998
.
Lymphocytes in the human gastric mucosa during Helicobacter pylori have a T helper cell 1 phenotype.
Gastroenterology
114
:
482
492
.
52
D’Elios
,
M. M.
,
M.
Manghetti
,
M.
De Carli
,
F.
Costa
,
C. T.
Baldari
,
D.
Burroni
,
J. L.
Telford
,
S.
Romagnani
,
G.
Del Prete
.
1997
.
T helper 1 effector cells specific for Helicobacter pylori in the gastric antrum of patients with peptic ulcer disease.
J. Immunol.
158
:
962
967
.
53
Osaki
,
L. H.
,
K. A.
Bockerstett
,
C. F.
Wong
,
E. L.
Ford
,
B. B.
Madison
,
R. J.
DiPaolo
,
J. C.
Mills
.
2019
.
Interferon-γ directly induces gastric epithelial cell death and is required for progression to metaplasia.
J. Pathol.
247
:
513
523
.
54
Kraft
,
M.
,
S.
Riedel
,
C.
Maaser
,
T.
Kucharzik
,
A.
Steinbuechel
,
W.
Domschke
,
N.
Luegering
.
2001
.
IFN-gamma synergizes with TNF-alpha but not with viable H. pylori in up-regulating CXC chemokine secretion in gastric epithelial cells.
Clin. Exp. Immunol.
126
:
474
481
.
55
Mitchell
,
D. J.
,
H. Q.
Huynh
,
P. J.
Ceponis
,
N. L.
Jones
,
P. M.
Sherman
.
2004
.
Helicobacter pylori disrupts STAT1-mediated gamma interferon-induced signal transduction in epithelial cells.
Infect. Immun.
72
:
537
545
.
56
Allison
,
C. C.
,
J.
Ferrand
,
L.
McLeod
,
M.
Hassan
,
M.
Kaparakis-Liaskos
,
A.
Grubman
,
P. S.
Bhathal
,
A.
Dev
,
W.
Sievert
,
B. J.
Jenkins
,
R. L.
Ferrero
.
2013
.
Nucleotide oligomerization domain 1 enhances IFN-γ signaling in gastric epithelial cells during Helicobacter pylori infection and exacerbates disease severity.
J. Immunol.
190
:
3706
3715
.
57
Obonyo
,
M.
,
D. G.
Guiney
,
J.
Harwood
,
J.
Fierer
,
S. P.
Cole
.
2002
.
Role of gamma interferon in Helicobacter pylori induction of inflammatory mediators during murine infection.
Infect. Immun.
70
:
3295
3299
.
58
Sawai
,
N.
,
M.
Kita
,
T.
Kodama
,
T.
Tanahashi
,
Y.
Yamaoka
,
Y.
Tagawa
,
Y.
Iwakura
,
J.
Imanishi
.
1999
.
Role of gamma interferon in Helicobacter pylori-induced gastric inflammatory responses in a mouse model.
Infect. Immun.
67
:
279
285
.
59
Shimada
,
M.
,
K.
Ina
,
K.
Kyokane
,
A.
Imada
,
H.
Yamaguchi
,
Y.
Nishio
,
M.
Hayakawa
,
Y.
Iinuma
,
M.
Ohta
,
T.
Ando
,
K.
Kusugami
.
2002
.
Upregulation of mucosal soluble fas ligand and interferon-gamma may be involved in ulcerogenesis in patients with Helicobacter pylori-positive gastric ulcer.
Scand. J. Gastroenterol.
37
:
501
511
.
60
Kang
,
W.
,
S.
Rathinavelu
,
L. C.
Samuelson
,
J. L.
Merchant
.
2005
.
Interferon gamma induction of gastric mucous neck cell hypertrophy.
Lab. Invest.
85
:
702
715
.
61
Qiao
,
X. T.
,
J. W.
Ziel
,
W.
McKimpson
,
B. B.
Madison
,
A.
Todisco
,
J. L.
Merchant
,
L. C.
Samuelson
,
D. L.
Gumucio
.
2007
.
Prospective identification of a multilineage progenitor in murine stomach epithelium.
Gastroenterology
133
:
1989
1998
.
62
McGeachy
,
M. J.
,
D. J.
Cua
,
S. L.
Gaffen
.
2019
.
The IL-17 family of cytokines in health and disease.
Immunity
50
:
892
906
.
63
Luzza
,
F.
,
T.
Parrello
,
G.
Monteleone
,
L.
Sebkova
,
M.
Romano
,
R.
Zarrilli
,
M.
Imeneo
,
F.
Pallone
.
2000
.
Up-regulation of IL-17 is associated with bioactive IL-8 expression in Helicobacter pylori-infected human gastric mucosa.
J. Immunol.
165
:
5332
5337
.
64
Mizuno
,
T.
,
T.
Ando
,
K.
Nobata
,
T.
Tsuzuki
,
O.
Maeda
,
O.
Watanabe
,
M.
Minami
,
K.
Ina
,
K.
Kusugami
,
R. M.
Peek
,
H.
Goto
.
2005
.
Interleukin-17 levels in Helicobacter pylori-infected gastric mucosa and pathologic sequelae of colonization.
World J. Gastroenterol.
11
:
6305
6311
.
65
Awane
,
M.
,
P. G.
Andres
,
D. J.
Li
,
H. C.
Reinecker
.
1999
.
NF-kappa B-inducing kinase is a common mediator of IL-17-, TNF-alpha-, and IL-1 beta-induced chemokine promoter activation in intestinal epithelial cells.
J. Immunol.
162
:
5337
5344
.
66
Hartupee
,
J.
,
C.
Liu
,
M.
Novotny
,
X.
Li
,
T.
Hamilton
.
2007
.
IL-17 enhances chemokine gene expression through mRNA stabilization.
J. Immunol.
179
:
4135
4141
.
67
Hartupee
,
J.
,
C.
Liu
,
M.
Novotny
,
D.
Sun
,
X.
Li
,
T. A.
Hamilton
.
2009
.
IL-17 signaling for mRNA stabilization does not require TNF receptor-associated factor 6.
J. Immunol.
182
:
1660
1666
.
68
Liu
,
C.
,
W.
Qian
,
Y.
Qian
,
N. V.
Giltiay
,
Y.
Lu
,
S.
Swaidani
,
S.
Misra
,
L.
Deng
,
Z. J.
Chen
,
X.
Li
.
2009
.
Act1, a U-box E3 ubiquitin ligase for IL-17 signaling. [Published erratum appears in 2010 Sci. Signal. 3: er3.]
Sci. Signal.
2
:
ra63
.
69
Zepp
,
J. A.
,
C.
Liu
,
W.
Qian
,
L.
Wu
,
M. F.
Gulen
,
Z.
Kang
,
X.
Li
.
2012
.
Cutting edge: TNF receptor-associated factor 4 restricts IL-17-mediated pathology and signaling processes.
J. Immunol.
189
:
33
37
.
70
Wu
,
L.
,
X.
Chen
,
J.
Zhao
,
B.
Martin
,
J. A.
Zepp
,
J. S.
Ko
,
C.
Gu
,
G.
Cai
,
W.
Ouyang
,
G.
Sen
, et al
.
2015
.
A novel IL-17 signaling pathway controlling keratinocyte proliferation and tumorigenesis via the TRAF4-ERK5 axis.
J. Exp. Med.
212
:
1571
1587
.
71
Chen
,
X.
,
G.
Cai
,
C.
Liu
,
J.
Zhao
,
C.
Gu
,
L.
Wu
,
T. A.
Hamilton
,
C. J.
Zhang
,
J.
Ko
,
L.
Zhu
, et al
.
2019
.
IL-17R-EGFR axis links wound healing to tumorigenesis in Lrig1+ stem cells.
J. Exp. Med.
216
:
195
214
.
72
Zhu
,
S.
,
W.
Pan
,
P.
Shi
,
H.
Gao
,
F.
Zhao
,
X.
Song
,
Y.
Liu
,
L.
Zhao
,
X.
Li
,
Y.
Shi
,
Y.
Qian
.
2010
.
Modulation of experimental autoimmune encephalomyelitis through TRAF3-mediated suppression of interleukin 17 receptor signaling.
J. Exp. Med.
207
:
2647
2662
.
73
Eyerich
,
K.
,
V.
Dimartino
,
A.
Cavani
.
2017
.
IL-17 and IL-22 in immunity: driving protection and pathology.
Eur. J. Immunol.
47
:
607
614
.
74
Dixon
,
B. R.
,
J. N.
Radin
,
M. B.
Piazuelo
,
D. C.
Contreras
,
H. M.
Algood
.
2016
.
IL-17a and IL-22 induce expression of antimicrobials in gastrointestinal epithelial cells and may contribute to epithelial cell defense against Helicobacter pylori.
PLoS One
11
: e0148514.
75
Algood
,
H. M.
,
S. S.
Allen
,
M. K.
Washington
,
R. M.
Peek
Jr.
,
G. G.
Miller
,
T. L.
Cover
.
2009
.
Regulation of gastric B cell recruitment is dependent on IL-17 receptor A signaling in a model of chronic bacterial infection.
J. Immunol.
183
:
5837
5846
.
76
Li
,
X. F.
,
M.
Shen
,
J. W.
Cai
,
Y. Q.
Zeng
,
M.
Li
,
G. L.
Yang
,
X. M.
Xu
,
Y. Y.
Hu
.
2015
.
Association of interleukin-17 gene polymorphisms and Helicobacter pylori infection with gastric cancer susceptibility: a cumulative and comprehensive meta-analysis.
Int. J. Clin. Exp. Med.
8
:
17623
17633
.
77
Zhuang
,
Y.
,
P.
Cheng
,
X. F.
Liu
,
L. S.
Peng
,
B. S.
Li
,
T. T.
Wang
,
N.
Chen
,
W. H.
Li
,
Y.
Shi
,
W.
Chen
, et al
.
2015
.
A pro-inflammatory role for Th22 cells in Helicobacter pylori-associated gastritis.
Gut
64
:
1368
1378
.
78
Chen
,
J. P.
,
M. S.
Wu
,
S. H.
Kuo
,
F.
Liao
.
2014
.
IL-22 negatively regulates Helicobacter pylori-induced CCL20 expression in gastric epithelial cells.
PLoS One
9
: e97350.
79
Lv
,
Y. P.
,
P.
Cheng
,
J. Y.
Zhang
,
F. Y.
Mao
,
Y. S.
Teng
,
Y. G.
Liu
,
H.
Kong
,
X. L.
Wu
,
C. J.
Hao
,
B.
Han
, et al
.
2019
.
Helicobacter pylori-induced matrix metallopeptidase-10 promotes gastric bacterial colonization and gastritis.
Science
5
:
eaau6547
.
80
Madden
,
K. B.
,
L.
Whitman
,
C.
Sullivan
,
W. C.
Gause
,
J. F.
Urban
Jr.
,
I. M.
Katona
,
F. D.
Finkelman
,
T.
Shea-Donohue
.
2002
.
Role of STAT6 and mast cells in IL-4- and IL-13-induced alterations in murine intestinal epithelial cell function.
J. Immunol.
169
:
4417
4422
.
81
Karttunen
,
R.
,
T.
Karttunen
,
H. P.
Ekre
,
T. T.
MacDonald
.
1995
.
Interferon gamma and interleukin 4 secreting cells in the gastric antrum in Helicobacter pylori positive and negative gastritis.
Gut
36
:
341
345
.
82
Smythies
,
L. E.
,
K. B.
Waites
,
J. R.
Lindsey
,
P. R.
Harris
,
P.
Ghiara
,
P. D.
Smith
.
2000
.
Helicobacter pylori-induced mucosal inflammation is Th1 mediated and exacerbated in IL-4, but not IFN-gamma, gene-deficient mice.
J. Immunol.
165
:
1022
1029
.
83
Mattapallil
,
J. J.
,
S.
Dandekar
,
D. R.
Canfield
,
J. V.
Solnick
.
2000
.
A predominant Th1 type of immune response is induced early during acute Helicobacter pylori infection in rhesus macaques.
Gastroenterology
118
:
307
315
.
84
Yamaoka
,
Y.
,
K.
Yamauchi
,
H.
Ota
,
A.
Sugiyama
,
S.
Ishizone
,
D. Y.
Graham
,
F.
Maruta
,
M.
Murakami
,
T.
Katsuyama
.
2005
.
Natural history of gastric mucosal cytokine expression in Helicobacter pylori gastritis in Mongolian gerbils.
Infect. Immun.
73
:
2205
2212
.
85
Eskandari-Nasab
,
E.
,
A.
Sepanjnia
,
M.
Moghadampour
,
M.
Hadadi-Fishani
,
A.
Rezaeifar
,
A.
Asadi-Saghandi
,
B.
Sadeghi-Kalani
,
M. D.
Manshadi
,
F.
Pourrajab
,
H.
Pourmasoumi
.
2013
.
Circulating levels of interleukin (IL)-12 and IL-13 in Helicobacter pylori-infected patients, and their associations with bacterial CagA and VacA virulence factors.
Scand. J. Infect. Dis.
45
:
342
349
.
86
el-Omar
,
E. M.
,
I. D.
Penman
,
J. E.
Ardill
,
R. S.
Chittajallu
,
C.
Howie
,
K. E.
McColl
.
1995
.
Helicobacter pylori infection and abnormalities of acid secretion in patients with duodenal ulcer disease.
Gastroenterology
109
:
681
691
.
87
Martinez
,
V.
,
A. P.
Curi
,
B.
Torkian
,
J. M.
Schaeffer
,
H. A.
Wilkinson
,
J. H.
Walsh
,
Y.
Taché
.
1998
.
High basal gastric acid secretion in somatostatin receptor subtype 2 knockout mice.
Gastroenterology
114
:
1125
1132
.
88
Zavros
,
Y.
,
S.
Rathinavelu
,
J. Y.
Kao
,
A.
Todisco
,
J.
Del Valle
,
J. V.
Weinstock
,
M. J.
Low
,
J. L.
Merchant
.
2003
.
Treatment of Helicobacter gastritis with IL-4 requires somatostatin.
Proc. Natl. Acad. Sci. USA
100
:
12944
12949
.
89
Petersen
,
C. P.
,
A. R.
Meyer
,
C.
De Salvo
,
E.
Choi
,
C.
Schlegel
,
A.
Petersen
,
A. C.
Engevik
,
N.
Prasad
,
S. E.
Levy
,
R. S.
Peebles
, et al
.
2018
.
A signalling cascade of IL-33 to IL-13 regulates metaplasia in the mouse stomach.
Gut
67
:
805
817
.
90
Marotti
,
B.
,
A.
Rocco
,
P.
De Colibus
,
D.
Compare
,
G.
de Nucci
,
S.
Staibano
,
F.
Tatangelo
,
M.
Romano
,
G.
Nardone
.
2008
.
Interleukin-13 mucosal production in Helicobacter pylori-related gastric diseases.
Dig. Liver Dis.
40
:
240
247
.
91
Raghavan
,
S.
,
M.
Fredriksson
,
A. M.
Svennerholm
,
J.
Holmgren
,
E.
Suri-Payer
.
2003
.
Absence of CD4+CD25+ regulatory T cells is associated with a loss of regulation leading to increased pathology in Helicobacter pylori-infected mice.
Clin. Exp. Immunol.
132
:
393
400
.
92
Rad
,
R.
,
L.
Brenner
,
S.
Bauer
,
S.
Schwendy
,
L.
Layland
,
C. P.
da Costa
,
W.
Reindl
,
A.
Dossumbekova
,
M.
Friedrich
,
D.
Saur
, et al
.
2006
.
CD25+/Foxp3+ T cells regulate gastric inflammation and Helicobacter pylori colonization in vivo.
Gastroenterology
131
:
525
537
.
93
Jang
,
T. J.
2010
.
The number of Foxp3-positive regulatory T cells is increased in Helicobacter pylori gastritis and gastric cancer.
Pathol. Res. Pract.
206
:
34
38
.
94
Kandulski
,
A.
,
P.
Malfertheiner
,
T.
Wex
.
2010
.
Role of regulatory T-cells in H. pylori-induced gastritis and gastric cancer.
Anticancer Res.
30
:
1093
1103
.
95
Raghavan
,
S.
,
M.
Quiding-Järbrink
.
2012
.
Immune modulation by regulatory T cells in Helicobacter pylori-associated diseases.
Endocr. Metab. Immune Disord. Drug Targets
12
:
71
85
.
96
Raghavan
,
S.
,
E.
Suri-Payer
,
J.
Holmgren
.
2004
.
Antigen-specific in vitro suppression of murine Helicobacter pylori-reactive immunopathological T cells by CD4CD25 regulatory T cells.
Scand. J. Immunol.
60
:
82
88
.
97
Cook
,
K. W.
,
D. P.
Letley
,
R. J.
Ingram
,
E.
Staples
,
H.
Skjoldmose
,
J. C.
Atherton
,
K.
Robinson
.
2014
.
CCL20/CCR6-mediated migration of regulatory T cells to the Helicobacter pylori-infected human gastric mucosa.
Gut
63
:
1550
1559
.
98
Vignali
,
D. A.
,
L. W.
Collison
,
C. J.
Workman
.
2008
.
How regulatory T cells work.
Nat. Rev. Immunol.
8
:
523
532
.
99
Sojka
,
D. K.
,
Y. H.
Huang
,
D. J.
Fowell
.
2008
.
Mechanisms of regulatory T-cell suppression - a diverse arsenal for a moving target.
Immunology
124
:
13
22
.
100
Szaflarska
,
A.
,
A.
Szczepanik
,
M.
Siedlar
,
A.
Czupryna
,
M.
Sierzega
,
T.
Popiela
,
M.
Zembala
.
2009
.
Preoperative plasma level of IL-10 but not of proinflammatory cytokines is an independent prognostic factor in patients with gastric cancer.
Anticancer Res.
29
:
5005
5012
.
101
Chen
,
L.
,
Y.
Shi
,
X.
Zhu
,
W.
Guo
,
M.
Zhang
,
Y.
Che
,
L.
Tang
,
X.
Yang
,
Q.
You
,
Z.
Liu
.
2019
.
IL-10 secreted by cancer-associated macrophages regulates proliferation and invasion in gastric cancer cells via c-Met/STAT3 signaling.
Oncol. Rep.
42
:
595
604
.
102
Batlle
,
E.
,
J.
Massagué
.
2019
.
Transforming growth factor-β signaling in immunity and cancer.
Immunity
50
:
924
940
.
103
Bonnans
,
C.
,
J.
Chou
,
Z.
Werb
.
2014
.
Remodelling the extracellular matrix in development and disease.
Nat. Rev. Mol. Cell Biol.
15
:
786
801
.
104
Sun
,
N.
,
A.
Taguchi
,
S.
Hanash
.
2016
.
Switching roles of TGF-β in cancer development: implications for therapeutic target and biomarker studies.
J. Clin. Med.
DOI: 10.3390/jcm5120109.
105
Hahm
,
K. B.
,
K. M.
Lee
,
Y. B.
Kim
,
W. S.
Hong
,
W. H.
Lee
,
S. U.
Han
,
M. W.
Kim
,
B. O.
Ahn
,
T. Y.
Oh
,
M. H.
Lee
, et al
.
2002
.
Conditional loss of TGF-beta signalling leads to increased susceptibility to gastrointestinal carcinogenesis in mice.
Aliment. Pharmacol. Ther.
16
(
s2
Suppl. 2
)
115
127
.
106
Wang
,
J. K.
,
W. J.
Wang
,
H. Y.
Cai
,
B. B.
Du
,
P.
Mai
,
L. J.
Zhang
,
W.
Ma
,
Y. G.
Hu
,
S. F.
Feng
,
G. Y.
Miao
.
2018
.
MFAP2 promotes epithelial-mesenchymal transition in gastric cancer cells by activating TGF-β/SMAD2/3 signaling pathway.
OncoTargets Ther.
11
:
4001
4017
.
107
Nakamura
,
M.
,
M.
Katano
,
A.
Kuwahara
,
K.
Fujimoto
,
K.
Miyazaki
,
T.
Morisaki
,
M.
Mori
.
1998
.
Transforming growth factor beta1 (TGF-beta1) is a preoperative prognostic indicator in advanced gastric carcinoma.
Br. J. Cancer
78
:
1373
1378
.
108
Maehara
,
Y.
,
Y.
Kakeji
,
A.
Kabashima
,
Y.
Emi
,
A.
Watanabe
,
K.
Akazawa
,
H.
Baba
,
S.
Kohnoe
,
K.
Sugimachi
.
1999
.
Role of transforming growth factor-beta 1 in invasion and metastasis in gastric carcinoma.
J. Clin. Oncol.
17
:
607
614
.
109
Ebert
,
M. P.
,
J.
Yu
,
S.
Miehlke
,
G.
Fei
,
U.
Lendeckel
,
K.
Ridwelski
,
M.
Stolte
,
E.
Bayerdörffer
,
P.
Malfertheiner
.
2000
.
Expression of transforming growth factor beta-1 in gastric cancer and in the gastric mucosa of first-degree relatives of patients with gastric cancer.
Br. J. Cancer
82
:
1795
1800
.
110
Pak
,
K. H.
,
D. H.
Kim
,
H.
Kim
,
D. H.
Lee
,
J. H.
Cheong
.
2016
.
Differences in TGF-β1 signaling and clinicopathologic characteristics of histologic subtypes of gastric cancer. [Published erratum appears in 2016 BMC Cancer. 16: 99.]
BMC Cancer
16
:
60
.
111
Zuo
,
Z. K.
,
Y.
Gong
,
X. H.
Chen
,
F.
Ye
,
Z. M.
Yin
,
Q. N.
Gong
,
J. S.
Huang
.
2017
.
TGFβ1-Induced LncRNA UCA1 upregulation promotes gastric cancer invasion and migration.
DNA Cell Biol.
36
:
159
167
.
112
Jeong
,
M. H.
,
S. Y.
Park
,
S. H.
Lee
,
J.
Seo
,
J. Y.
Yoo
,
S. H.
Park
,
M. J.
Kim
,
S.
Lee
,
S.
Jang
,
H. K.
Choi
, et al
.
2019
.
EPB41L5 mediates TGFβ-induced metastasis of gastric cancer.
Clin. Cancer Res.
25
:
3617
3629
.

The authors have no financial conflicts of interest.