IL-4 has been extensively studied in the context of its role in immunity. Accumulating evidence indicates, however, that it also plays a critical role in higher functions of the normal brain, such as memory and learning. In this review, we summarize current knowledge of the basic immunology of IL-4, describe how and where this cytokine appears to operate in normal brain function, and propose a hypothesis concerning its potential role in neurological pathologies.

The brain is frequently studied in isolation from the immune system. The principal reason for this is clear: conventional wisdom has long held that the brain is shielded from immune-cell infiltration by the blood–brain barrier (BBB). When this protective interface is breached and the immune system freely interacts with the brain, it frequently results in autoimmune attacks and other debilitating immune-related conditions. In reality, however, neuroimmune interactions appear to be crucial for everyday brain function. Mice in which adaptive immunity is absent or acutely suppressed exhibit cognitive impairment, which is expressed in their inability to perform spatial learning tasks, a defect that is reversible upon restoration of the T cell pool (13). One likely location for neuroimmune interactions is the subarachnoid space, a cerebrospinal fluid-filled compartment of the meninges. Healthy human cerebrospinal fluid contains ∼150,000 leukocytes (∼10,000 in the C57B6 mouse [our laboratory's unpublished observations]), most of which are central memory T cells (4). A recent study from our laboratory showed that performance of a learning and memory task is followed by an increase in the numbers and activation of T cells in the meninges. Moreover, administration of anti-VLA4, which prevents normal extravasation of T cells (and monocytes) into the cerebrospinal fluid, produced a cognitive impairment similar to that seen in T cell-deficient mice (5).

T cells in the cerebrospinal fluid appear ideally positioned to communicate with the brain. In healthy individuals, however, T cells do not penetrate the brain parenchyma, and any such communication must be mediated through a soluble messenger. We recently showed that T cell-derived IL-4 is a critical participant in higher brain functions such as memory and learning (5). Mice that lack IL-4 demonstrate cognitive impairment in spatial learning tasks, and this can be reversed by transplantation of IL-4–competent bone marrow (5). In this article, we focus on the basic immunology of IL-4 as it pertains to the CNS, and in particular to the question of how and where it operates to influence cognition. We end with a review of the literature on the role of IL-4 in several neurological diseases.

IL-4 is a cytokine that functions as a potent regulator of immunity secreted primarily by mast cells, Th2 cells, eosinophils, and basophils. Initially identified by Howard and Paul (6) as a comitogen of B cells, IL-4 was subsequently shown to be an important player in leukocyte survival under both physiological and pathological conditions (7, 8), such as Th2 cell-mediated immunity (9, 10), IgE class switching in B cells (11), and tissue repair and homeostasis through “alternative” macrophage activation (12). Although granulocytes and type 2 innate lymphoid cells (13) are capable of producing Th2 cytokines, the majority of currently available literature, including our own studies, focus on Th2 T cells.

The effect of IL-4 signaling is mediated through the IL-4R α-chain (IL-4Rα). Upon binding to its ligand, IL-4Rα dimerizes either with the common γ-chain to produce the type 1 signaling complex, located mainly on hematopoietic cells, or with the IL-13Rα1 to produce the type 2 complex, which is expressed also on nonhematopoietic cells (14, 15). The type 1 signaling complex is critical for Th2 skewing of T cells and the development of alternatively activated macrophages (AAMΦs), whereas the type 2 complex plays a role in nonhematopoietic responses to IL-4 and IL-13, for example, airway hyperreactivity and mucous production (16). The role of IL-13 in CNS function is understudied and merits further investigation.

Upon activation, the type 1 complex signals through Janus family kinases (JAK1 and JAK3), which phosphorylate and create docking sites for the transcription factor STAT6, which then dimerizes and translocates to the cell nucleus. Among its other actions, STAT6 promotes transcription of GATA3 (a Th2 cell inducer) and MHCII (myeloid and B cells), and induces IgE class switching in B cells (11, 1719). JAK1 also phosphorylates insulin receptor substrate-1 and -2, which become activated and promote survival and growth through the PI3/AKT, PKB/mTOR, and other pathways (20).

The type 2 receptors also signal through JAK family kinases (JAK1 and TYK2), but are not expressed by T cells, and instead are used by nonhematopoietic cells such as endothelial cells and fibroblasts to respond to IL-4. As with type 1, much of the message of type 2 receptors is conveyed by STAT6, which is phosphorylated and translocates to the nucleus upon ligand binding. Type 2 receptors also serve as receptors for IL-13, a cytokine with similarities to IL-4, and that first binds with the IL-13Rα1 and then dimerizes with IL-4Rα to produce the familiar signaling cascade (Fig. 1).

FIGURE 1.

IL-4 signaling pathways. After IL-4 binding IL-4Rα, the IL-4R is created by dimerization with the common γ-chain (γc) to create the type 1 signaling complex or with IL-13Rα1 to create the type 2 complex. Both receptors signal through STAT6, which is phosphorylated, dimerizes, and traffics to the nucleus to function as a transcription factor for Th2, IgE, and AAMΦ-associated genes. The type 1 receptor also activates IRS1 and/or IRS2, leading to increased mitogenesis and inhibition of apoptosis through multiple signaling pathways. The type 2 complex also responds to IL-13, and it can signal other STAT molecules (i.e., STAT3) through the JAK family kinase TYK2.

FIGURE 1.

IL-4 signaling pathways. After IL-4 binding IL-4Rα, the IL-4R is created by dimerization with the common γ-chain (γc) to create the type 1 signaling complex or with IL-13Rα1 to create the type 2 complex. Both receptors signal through STAT6, which is phosphorylated, dimerizes, and traffics to the nucleus to function as a transcription factor for Th2, IgE, and AAMΦ-associated genes. The type 1 receptor also activates IRS1 and/or IRS2, leading to increased mitogenesis and inhibition of apoptosis through multiple signaling pathways. The type 2 complex also responds to IL-13, and it can signal other STAT molecules (i.e., STAT3) through the JAK family kinase TYK2.

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Findings by our group and others have demonstrated a fundamental role for T cells in cognition and brain homeostasis (2, 2124). Mice that lack T lymphocytes exhibit cognitive impairment in learning tasks on the Morris water maze (MWM). An established behavior paradigm, the MWM takes place over a week where mice are placed once daily in a large plastic pool in which a platform is submerged in opaque water. Salient visual cues are supplied in the testing room that allow the mice to gradually learn the location of the platform. Over the course of several days, a healthy mouse will commit this location to memory and exhibit progressively faster escape latency to the platform (25). Although T cell-deficient mice spend considerably more time searching for the platform, MWM performance can be restored almost to the level of wild-type mice by adoptive transfer of wild-type T cells or by bone marrow transplantation from wild-type to immune-deficient counterparts. In addition to their spatial learning deficits, mice that lack both T and B cells (SCID, nude, or Rag1−/− mice) exhibit reduction of adult neurogenesis (2, 24, 26), an ongoing physiological process in which new neurons are generated in specific zones of the adult brain (27). Wolf et al. (24) further identified CD4+ T cells as the key immune population responsible for both adult neurogenesis and cognitive performance.

Inflammatory cytokines such IL-1β and TNF have been extensively studied in the brain, where they exert a negative effect on cognitive behavior, characterized by sickness, depression, and stress (2830). We recently discovered that the effect of IL-4 on cognition, in contrast, is beneficial. After mice undergo training in the MWM, their meningeal T cells become activated and produce more IL-4 than untrained controls (5). Absence of the ability to produce IL-4 in response to learning has conspicuous consequences, as observed in the severe learning defects exhibited by IL-4−/− mice (5). These defects can be reversed by transplantation with wild-type bone marrow or adoptive transfer of IL-4–competent T cells, whereas both T cells and transplanted bone marrow derived from IL-4−/− mice are ineffective. Furthermore, wild-type mice transplanted with IL-4−/− bone marrow subsequently show learning impairment, reinforcing the role of IL-4 in cognition and demonstrating its dynamic nature (5).

The previously discussed findings clearly show that T cell-derived IL-4 has a profound effect on cognition, but its mechanism of action, given the stringent BBB, is unclear. Astrocytes, as described later, respond to IL-4 signaling and might serve as a mediator between the immune effector cells and the nervous responders. This possibility is supported by the fact that in wild-type mice, but not in IL-4 knockout mice, training in the MWM is followed by astrocytic production of brain-derived neurotrophic factor (BDNF) (5). This protein, which is responsible for growth and survival of neurons and for increased neuronal arborization of dendrites, has been shown to have a positive effect on learning, and its absence in IL-4 knockout mice might explain their cognitive defects (31, 32).

Another possible target for IL-4 is the meningeal myeloid compartment, where lack of IL-4 creates a proinflammatory meningeal immune response (5). Meningeal myeloid cells (CD11b+) in SCID mice produce more TNF than their wild-type counterparts (5). Adoptive transfer of wild-type T cells, but not of IL-4 knockout T cells, reduces this TNF production (5). Thus, IL-4 might be exerting its effect through an anti-inflammatory M2-skew (alternative activation) of meningeal macrophages, shown to be beneficial after CNS injury (33) and required for learning (34). Administration of M2-skewed macrophages, either intracerebroventricularly (i.c.v.) or i.v., improves MWM performance in immunocompromised animals (34). Whether these procognitive effects of T cells through astrocytes and through M2 macrophages are separate or linked processes remains to be investigated, but in either case, they provide interesting avenues for productive neuroimmune communication.

IL-4 plays important roles in a myriad of cellular events, making it difficult to study its effects, particularly in vivo, on any one system. Although this review focuses on its neurological functions, most of what is known about IL-4 comes from studies of peripheral immune cells, such as macrophages and lymphocytes. Therefore, in discussing the cellular targets of this cytokine, we will extrapolate from those cell types where appropriate.

The earliest studies of IL-4 in macrophages showed that it acted as an anti-inflammatory agent when administered concurrently or shortly after an inflammatory stimulus, and was capable of downregulating the production of inflammatory cytokines such as TNF (35). IL-4 is not purely an anti-inflammatory agent, however, as priming of macrophages with IL-4 followed by proinflammatory stimulation can result in an enhanced inflammatory response (36). Studies in vivo showed that chronic high dosage or transgenic overproduction of IL-4 results in accumulation of AAMΦs, increased IFN-γ expression, decreased proinflammatory cytokine production, histiocytosis, erythrophagocytosis, extramedullary hematopoiesis, and weight loss (37).

These data suggest that the in vivo effects of IL-4 are complex, well regulated, dependent on the local environment, and that they probably mediate different processes simultaneously in different tissues. The situation is even more complex in the context of the brain, which is clearly affected by IL-4; however, little is known about the ability of this cytokine to access the parenchyma or the nature of its effects on target cells. Microglia and astrocytes within the CNS have been studied with regard to IL-4, but the possible role of IL-4 in directly stimulating neurons and oligodendrocytes is poorly understood.

As mentioned earlier, BDNF production by astrocytes might provide a mechanism whereby IL-4 influences cognition (5). BDNF may not be the only participating factor, however, as IL-4 can also elicit astrocytic expression of other CNS growth factors, such as nerve growth factor (38, 39). This function of IL-4 is not unexpected, as it can also induce other growth and survival pathways in the periphery (40). Astrocytes clearly respond to IL-4, but their receptor expression and the factors that regulate receptor expression are not well understood. In the epileptic brain, astrocytes express high levels of IL-4Rα, but do not express the common γ-chain (41), suggesting they may signal through the type 2 complex (the more typical receptor for nonhematopoietic cells; Fig. 1). IL-4 can exert both proinflammatory and anti-inflammatory effects on astrocytes, depending on the treatment and timing paradigm. In primary mouse astrocytes, pretreatment with IL-4 decreases subsequent production of NO and inducible NO synthase protein, as well as secretion of TNF upon LPS stimulation (38). Similarly, concurrent treatment of primary fetal human astrocytes with IL-4 attenuates NO production by those cells when stimulated with IL-1β, TNF, or IFN-γ (42). In another study, however, IL-1β–pretreated primary mouse astrocytes demonstrated enhanced IL-6 production when subsequently treated with IL-4, whereas treatment with IL-10 and dexamethasone yielded immunosuppressive effects. The same study showed that IL-1β induces astrocytic IL-4Rα expression (43). Interestingly, both IFN-γ and IL-4 can elicit neuroprotective phenotypes in astrocytes. Treatment with IFN-γ enhances the ability of astrocytes to clear extracellular glutamate (an excitatory neurotransmitter), an effect that is antagonized by IL-4 (44). However, conditioned medium from IL-4–treated astrocytes is neuroprotective in a dose-dependent manner, whereas the same is true for IFN-γ at low doses only (44). The findings of the latter study thus point to a complex interplay between these two canonical Th1 and Th2 cytokines in the context of neuroprotection. Altogether, these findings show that astrocytes have a relationship to IL-4 that is complex and merits further study.

Microglia are the brain’s equivalent of tissue-resident macrophages. Their lineage is similar to that of macrophages, although they engraft very early in development and maintain a self-renewing population throughout the life of the organism (45). However, when certain conditions are met, usually involving damage, new microglia-like cells from the monocyte lineage can be engrafted into the brain of an adult animal (46).

Microglia respond comparably to macrophages in skewing paradigms (M1 and the many variants of M2) (47, 48). These include expression changes of proteins such as YM1 and ARG1, typical of IL-4–treated macrophages. Like macrophages, microglia respond to IFN-γ priming and subsequent stimulation by upregulating NO production through induction of inducible NO synthase (49). Incubation with IL-4 before priming with IFN-γ or TNF, and subsequent stimulation with PMA, causes a dose-dependent decrease in NO production (49). Indeed, it has been shown that IL-4 exerts a neuroprotective effect via decreasing TNF and increasing IGF-1 (50). IL-4 also antagonizes IFN-γ–driven MHCII expression (51). However, IL-4 alone, after long-term exposure, also induces MHCII expression (50). CD200, a microglial regulatory protein, is expressed on neurons in an IL-4–dependent fashion, providing a possible mechanism for IL-4–mediated regulation of microglial activation. Neurons from IL-4−/− mice were found to be less effective than wild-type neurons in attenuating an inflammatory response, a result that was linked to lower CD200 expression on the IL-4−/− neurons (52). Another interesting finding was that IL-4–activated microglia can bias adult neural progenitor cells toward oligodendrogenesis (53). In addition, IL-4 was found to induce CD11c on microglia in vitro, a marker typically associated with dendritic cells (54). All in all, it seems that microglia and macrophages similarly respond to IL-4 signaling, and that absence of IL-4 heightens vulnerability to neuroinflammation. It remains unclear, however, whether IL-4 has a proinflammatory role in microglial biology, as it does in macrophages.

IL-4 has a well-established role in the pathology of allergy and other immunological diseases, where it is secreted by T cells to induce B cell activation and IgE class switching. Less well studied, but nevertheless also important, is its influence in other diseases, including neurological ones such as Alzheimer’s disease (AD), multiple sclerosis (MS), and glioblastoma multiforme (GBM).

Aging in humans and rodents is accompanied by steady cognitive decline. Among the contributors to this decline is an increase in baseline inflammation. The performance of aged mice in the MWM is impaired relative to that of younger adults, in correlation with proinflammatory changes in the hippocampal (55) and global (56) transcriptome (57). Proinflammatory cytokines, such as IL-1β, IL-6, and IL-18, are increased in the aged hippocampus and are known to affect long-term potentiation (LTP), a cellular mechanism of memory whereby the strength of neuronal connections is modified (5860).

The effects of IL-4 in aging have been reported in only a few publications, but the role of this cytokine in counteracting inflammatory changes is indisputable, and the increase in cytokines such as IL-1β and IL-6 observed in aging animals is accompanied by a decrease in hippocampal IL-4 (61). This decrease is functional, and direct i.c.v. administration of IL-4 rescues the LTP defects observed in aged mice (62). IL-4 can also counter the effects of IL-1β on LTP when coadministered i.c.v. (61). Interestingly, microglia become less sensitive to IL-4 in aged mice and tend to activate more readily, with resulting impairment of LTP (63, 64). These experiments suggest a potential role for IL-4 in countering age-related proinflammatory changes, although whether the inflammation itself derives from a lack of IL-4 signaling is not known. The cognitive impairment seen in aged mice might be partially explained by the increase in proinflammatory cytokines and a decrease in the amount of and sensitivity to the opposing cytokine IL-4, which, in turn, disrupts LTP and impairs learning.

Many of the same inflammatory processes that operate in aging contribute to the pathology of AD, such as IL-1β–related inflammation (65, 66). IL-4 treatment can reverse certain aspects of AD pathology in animal models (Fig. 2), as shown, for example, by the finding that viral gene delivery of IL-4 to the CNS of an AD mouse model alleviates several aspects of the disease (67).

FIGURE 2.

A working model of IL-4 function in the subarachnoid space after learning. After MWM training, T cells in the meninges become activated by a yet unknown mechanism and produce IL-4. IL-4 then may skew meningeal macrophages to M2, which have been shown to reverse cognitive defects of immunosuppressed mice. IL-4 additionally affects astrocytes, although it is unclear whether and how it crosses the BBB to do so. Other potential targets include microglia and neurons, although data are lacking to conclusively describe this response.

FIGURE 2.

A working model of IL-4 function in the subarachnoid space after learning. After MWM training, T cells in the meninges become activated by a yet unknown mechanism and produce IL-4. IL-4 then may skew meningeal macrophages to M2, which have been shown to reverse cognitive defects of immunosuppressed mice. IL-4 additionally affects astrocytes, although it is unclear whether and how it crosses the BBB to do so. Other potential targets include microglia and neurons, although data are lacking to conclusively describe this response.

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There is also a tendency toward microglial activation in AD. Microglia tend to switch from M2- to M1-like activation as AD progresses (68). The microglial regulatory molecules CD200 and CD200R are decreased in AD (69), leading to unchecked microglial activation. As described earlier, IL-4 regulates CD200/CD200R expression (52, 70), and one possible mechanism by which it exerts its effect in AD is by promoting CD200R expression on microglia, helping to quell their pathological activation (71). In addition to negating inflammatory mediators, IL-4 may confer direct benefit by inducing the IL-4–associated M2-type microglia, which have been shown in vitro to have superior amyloid-β clearance relative to M1 microglia (72, 73). In line with this, administration of amyloid-β–specific Th2 cells in the mouse model of AD improves spatial memory, decreases microglial plaque involvement, and reduces cerebral amyloid blood vessel pathology (74).

MS is a progressive demyelinating condition characterized by a relapsing and remitting course of neurological symptoms such as blurred vision, impaired balance, and paresthesias. As it progresses, MS can become increasingly debilitating and ultimately fatal. MS is often studied in rodents with experimental autoimmune encephalitis (EAE), an animal model for MS, which is induced in mice by adoptive transfer of CNS-reactive T cells or active immunization with CNS Ags. Studies of the severity of EAE in IL-4−/− mice relative to wild-type mice (75) point to a potentially protective role of IL-4 against the incidence and progression of MS.

The IL-4R is highly expressed on perivascular macrophages (76), pointing to the potential for IL-4 to regulate the myeloid compartment in animals with EAE. Microglia may help to protect the brain against autoimmunity by regulating themselves with local CNS-derived IL-4. Resting and EAE-derived microglia produce IL-4 and express Ym1 (an M2 marker), whereas infiltrating macrophages in EAE produce NO (an M1 marker) (48). Interestingly, replacement of IL-4−/− bone marrow by wild-type bone marrow does not suffice to reduce EAE severity to wild-type levels, pointing to the possibility of a brain-endogenous source of IL-4 (48). Furthermore, administration of skewed M2 cells can significantly reduce EAE severity, even when injected after disease onset in rats (77) or i.c.v. into mice (78). The molecular signaling of M2 cells was recently established further in the murine EAE model, and suggested that M2 cells can inhibit atypical EAE via SOCS3 signaling (79). These findings demonstrate the importance of myeloid skewing in MS, and suggest that IL-4 might coordinate a beneficial M2 response.

GBM is a devastating tumor with a 5-y survival rate of ∼3% (80). The role of IL-4 in cancer appears to differ from its role in other neurological diseases, in that it manifests somewhat contradictory protumor and antitumor effects depending on the tumor and the tissue type (81). Interestingly, the majority of GBM patient samples overexpress the IL-13Rα2 chain (82) and the IL-4Rα in culture (83, 84). In addition, GBM risk and outcome are altered by polymorphisms in these genes. There is a well-established inverse correlation between allergy, a disease process affected by IL-4, and GBM occurrence: individuals diagnosed with GBM are significantly less likely to report allergies (85, 86). This observation is supported by the finding that asthma-associated single nucleotide polymorphisms in the il4r, il13, and stat6 gene loci are also inversely correlated with occurrence of GBM (87, 88). Another study showed that certain polymorphisms in il4r correlate to improved GBM mortality rates (89).

These studies highlight the importance of IL-4 and IL-13 in GBM biology, but the mechanism responsible for their effect is poorly understood. Early studies demonstrated that IL-4 inhibits GBM xenograft growth in inducible IL-4ko cell lines (90) and when administered s.c. (91) or retrovirally (92). Other studies use adenoviral delivery of IL-4 under a hypoxia-inducible promoter in various GBM xenograft lines, showing marked regression of tumor growth and selective lysis of hypoxic cells after viral treatment (93, 94). IL-4 is typically thought to aid in tumor control by blocking angiogenesis (90, 95) or recruiting eosinophils (96, 97).

As tumors progress, macrophages become skewed from a proinflammatory M1 to a tumor-promoting M2 phenotype. M2 macrophages support tumor growth and survival, inducing angiogenesis (through production of vascular endothelial growth factor), creating an immunosuppressive environment, and encouraging invasiveness and metastasis (98, 99). In a nonbrain cancer model, IL-4 together with IL-10 and vascular endothelial growth factor are crucial to generation of the proinvasive M2 myeloid skew, and inhibition of IL-4Rα in vivo blocks macrophage polarization (100). Thus, IL-4 function in GBM might be dichotomous, being used by the tumor to create AAMΦs, but toxic when administered directly.

These studies collectively illustrate a crucial role for IL-4 in the regulation of brain immunity, with measureable downstream effects on spatial learning/memory and neurogenesis, and with implications for neurological disorders. From the data reviewed in this article, it is tempting to assume that an “alternative” IL-4–driven activation of the immune system supports brain function, whereas molecules with classic “proinflammatory” signals hinder it. This view may, however, be an oversimplification of complex neuroimmune interactions taking place in boundaries of the brain and in the brain parenchyma. Although proinflammatory cytokines have been implicated in the detrimental effects of sickness behavior, aging, and autoimmunity, it is likely that a proper balance in peripheral and brain immunity is required for optimal brain performance. In fact, certain cytokines associated with classical inflammation are required for many aspects of vital CNS function such as synaptic scaling through glial TNF (101) and the role of IL-6 in ensuring functional LTP in the hippocampus (102).

In times of stress and disease, the delicate balance in brain immunity is altered, with proinflammatory molecules produced to a high degree in response to a potential threat (28). Production of IL-4 by meningeal T cells and other cell types could therefore be viewed in terms of an evolutionary adaptation to restore balanced CNS function and cognition. New molecular and genetic tools that target IL-4, IL-13, and their receptors in specific cell types will advance the field and further our understanding on the precise roles of T cell-derived and non-T cell-derived IL-4 in the regulation of brain function.

Although replacing or even directly altering CNS cells represents a substantial technical challenge, in part because of the BBB, the immune system is more easily targeted by drugs and can even be replaced by means of bone marrow transplantation. Therefore, a better understanding of the effects of the immune system on CNS function will open new therapeutic avenues for diseases that have traditionally been approached as purely neurological, but that have important and treatable immune components (103).

We thank Shirley Smith and Nicola Watson for editing the manuscript. We thank the members of the Kipnis laboratory for valuable comments during multiple discussions of this work.

This work was supported by National Institute on Aging, National Institutes of Health Grant AG034113 (to J.K.).

Abbreviations used in this article:

     
  • AAMΦ

    alternatively activated macrophage

  •  
  • AD

    Alzheimer’s disease

  •  
  • BBB

    blood–brain barrier

  •  
  • BDNF

    brain-derived neurotrophic factor

  •  
  • EAE

    experimental autoimmune encephalitis

  •  
  • GBM

    glioblastoma multiforme

  •  
  • i.c.v.

    intracerebroventricularly

  •  
  • IL-4Rα

    IL-4R α-chain

  •  
  • LTP

    long-term potentiation

  •  
  • MS

    multiple sclerosis

  •  
  • MWM

    Morris water maze.

1
Cohen
H.
,
Ziv
Y.
,
Cardon
M.
,
Kaplan
Z.
,
Matar
M. A.
,
Gidron
Y.
,
Schwartz
M.
,
Kipnis
J.
.
2006
.
Maladaptation to mental stress mitigated by the adaptive immune system via depletion of naturally occurring regulatory CD4+CD25+ cells.
J. Neurobiol.
66
:
552
563
.
2
Ziv
Y.
,
Ron
N.
,
Butovsky
O.
,
Landa
G.
,
Sudai
E.
,
Greenberg
N.
,
Cohen
H.
,
Kipnis
J.
,
Schwartz
M.
.
2006
.
Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood.
Nat. Neurosci.
9
:
268
275
.
3
Brynskikh
A.
,
Warren
T.
,
Zhu
J.
,
Kipnis
J.
.
2008
.
Adaptive immunity affects learning behavior in mice.
Brain Behav. Immun.
22
:
861
869
.
4
Engelhardt
B.
,
Ransohoff
R. M.
.
2005
.
The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms.
Trends Immunol.
26
:
485
495
.
5
Derecki
N. C.
,
Cardani
A. N.
,
Yang
C. H.
,
Quinnies
K. M.
,
Crihfield
A.
,
Lynch
K. R.
,
Kipnis
J.
.
2010
.
Regulation of learning and memory by meningeal immunity: a key role for IL-4.
J. Exp. Med.
207
:
1067
1080
.
6
Howard
M.
,
Farrar
J.
,
Hilfiker
M.
,
Johnson
B.
,
Takatsu
K.
,
Hamaoka
T.
,
Paul
W. E.
.
1982
.
Identification of a T cell-derived b cell growth factor distinct from interleukin 2.
J. Exp. Med.
155
:
914
923
.
7
Hu-Li
J.
,
Shevach
E. M.
,
Mizuguchi
J.
,
Ohara
J.
,
Mosmann
T.
,
Paul
W. E.
.
1987
.
B cell stimulatory factor 1 (interleukin 4) is a potent costimulant for normal resting T lymphocytes.
J. Exp. Med.
165
:
157
172
.
8
Minshall
C.
,
Arkins
S.
,
Straza
J.
,
Conners
J.
,
Dantzer
R.
,
Freund
G. G.
,
Kelley
K. W.
.
1997
.
IL-4 and insulin-like growth factor-I inhibit the decline in Bcl-2 and promote the survival of IL-3-deprived myeloid progenitors.
J. Immunol.
159
:
1225
1232
.
9
Seder
R. A.
,
Paul
W. E.
,
Davis
M. M.
,
Fazekas de St Groth
B.
.
1992
.
The presence of interleukin 4 during in vitro priming determines the lymphokine-producing potential of CD4+ T cells from T cell receptor transgenic mice.
J. Exp. Med.
176
:
1091
1098
.
10
Hsieh
C. S.
,
Heimberger
A. B.
,
Gold
J. S.
,
O’Garra
A.
,
Murphy
K. M.
.
1992
.
Differential regulation of T helper phenotype development by interleukins 4 and 10 in an alpha beta T-cell-receptor transgenic system.
Proc. Natl. Acad. Sci. USA
89
:
6065
6069
.
11
Geha
R. S.
,
Jabara
H. H.
,
Brodeur
S. R.
.
2003
.
The regulation of immunoglobulin E class-switch recombination.
Nat. Rev. Immunol.
3
:
721
732
.
12
Gordon
S.
2003
.
Alternative activation of macrophages.
Nat. Rev. Immunol.
3
:
23
35
.
13
Wills-Karp
M.
,
Finkelman
F. D.
.
2011
.
Innate lymphoid cells wield a double-edged sword.
Nat. Immunol.
12
:
1025
1027
.
14
Nelms
K.
,
Keegan
A. D.
,
Zamorano
J.
,
Ryan
J. J.
,
Paul
W. E.
.
1999
.
The IL-4 receptor: signaling mechanisms and biologic functions.
Annu. Rev. Immunol.
17
:
701
738
.
15
Callard
R. E.
,
Matthews
D. J.
,
Hibbert
L.
.
1996
.
IL-4 and IL-13 receptors: are they one and the same?
Immunol. Today
17
:
108
110
.
16
Ramalingam
T. R.
,
Pesce
J. T.
,
Sheikh
F.
,
Cheever
A. W.
,
Mentink-Kane
M. M.
,
Wilson
M. S.
,
Stevens
S.
,
Valenzuela
D. M.
,
Murphy
A. J.
,
Yancopoulos
G. D.
, et al
.
2008
.
Unique functions of the type II interleukin 4 receptor identified in mice lacking the interleukin 13 receptor alpha1 chain.
Nat. Immunol.
9
:
25
33
.
17
Goenka
S.
,
Kaplan
M. H.
.
2011
.
Transcriptional regulation by STAT6.
Immunol. Res.
50
:
87
96
.
18
Gould
H. J.
,
Sutton
B. J.
.
2008
.
IgE in allergy and asthma today.
Nat. Rev. Immunol.
8
:
205
217
.
19
Lee
G. R.
,
Fields
P. E.
,
Griffin
T. J.
,
Flavell
R. A.
.
2003
.
Regulation of the Th2 cytokine locus by a locus control region.
Immunity
19
:
145
153
.
20
Luzina
I. G.
,
Keegan
A. D.
,
Heller
N. M.
,
Rook
G. A.
,
Shea-Donohue
T.
,
Atamas
S. P.
.
2012
.
Regulation of inflammation by interleukin-4: a review of “alternatives.”
J. Leukoc. Biol
.
In press
.
21
Kipnis
J.
,
Cohen
H.
,
Cardon
M.
,
Ziv
Y.
,
Schwartz
M.
.
2004
.
T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions.
Proc. Natl. Acad. Sci. USA
101
:
8180
8185
.
22
Hess
L. M.
,
Insel
K. C.
.
2007
.
Chemotherapy-related change in cognitive function: a conceptual model.
Oncol. Nurs. Forum
34
:
981
994
.
23
Staat
K.
,
Segatore
M.
.
2005
.
The phenomenon of chemo brain.
Clin. J. Oncol. Nurs.
9
:
713
721
.
24
Wolf
S. A.
,
Steiner
B.
,
Akpinarli
A.
,
Kammertoens
T.
,
Nassenstein
C.
,
Braun
A.
,
Blankenstein
T.
,
Kempermann
G.
.
2009
.
CD4-positive T lymphocytes provide a neuroimmunological link in the control of adult hippocampal neurogenesis.
J. Immunol.
182
:
3979
3984
.
25
Morris
R.
1984
.
Developments of a water-maze procedure for studying spatial learning in the rat.
J. Neurosci. Methods
11
:
47
60
.
26
Wolf
S. A.
,
Steiner
B.
,
Wengner
A.
,
Lipp
M.
,
Kammertoens
T.
,
Kempermann
G.
.
2009
.
Adaptive peripheral immune response increases proliferation of neural precursor cells in the adult hippocampus.
FASEB J.
23
:
3121
3128
.
27
Gage
F. H.
,
Ray
J.
,
Fisher
L. J.
.
1995
.
Isolation, characterization, and use of stem cells from the CNS.
Annu. Rev. Neurosci.
18
:
159
192
.
28
Dantzer
R.
,
O’Connor
J. C.
,
Freund
G. G.
,
Johnson
R. W.
,
Kelley
K. W.
.
2008
.
From inflammation to sickness and depression: when the immune system subjugates the brain.
Nat. Rev. Neurosci.
9
:
46
56
.
29
Couthouis
J.
,
Hart
M. P.
,
Shorter
J.
,
DeJesus-Hernandez
M.
,
Erion
R.
,
Oristano
R.
,
Liu
A. X.
,
Ramos
D.
,
Jethava
N.
,
Hosangadi
D.
, et al
.
2011
.
A yeast functional screen predicts new candidate ALS disease genes.
Proc. Natl. Acad. Sci. USA
108
:
20881
20890
.
30
Kelley
K. W.
,
Bluthé
R. M.
,
Dantzer
R.
,
Zhou
J. H.
,
Shen
W. H.
,
Johnson
R. W.
,
Broussard
S. R.
.
2003
.
Cytokine-induced sickness behavior.
Brain Behav. Immun.
17
(
Suppl. 1
):
S112
S118
.
31
Choy
K. H.
,
de Visser
Y.
,
Nichols
N. R.
,
van den Buuse
M.
.
2008
.
Combined neonatal stress and young-adult glucocorticoid stimulation in rats reduce BDNF expression in hippocampus: effects on learning and memory.
Hippocampus
18
:
655
667
.
32
Hall
J.
,
Thomas
K. L.
,
Everitt
B. J.
.
2000
.
Rapid and selective induction of BDNF expression in the hippocampus during contextual learning.
Nat. Neurosci.
3
:
533
535
.
33
Schwartz
M.
2010
.
“Tissue-repairing” blood-derived macrophages are essential for healing of the injured spinal cord: from skin-activated macrophages to infiltrating blood-derived cells?
Brain Behav. Immun.
24
:
1054
1057
.
34
Derecki
N. C.
,
Quinnies
K. M.
,
Kipnis
J.
.
2011
.
Alternatively activated myeloid (M2) cells enhance cognitive function in immune compromised mice.
Brain Behav. Immun.
25
:
379
385
.
35
Hart
P. H.
,
Vitti
G. F.
,
Burgess
D. R.
,
Whitty
G. A.
,
Piccoli
D. S.
,
Hamilton
J. A.
.
1989
.
Potential antiinflammatory effects of interleukin 4: suppression of human monocyte tumor necrosis factor alpha, interleukin 1, and prostaglandin E2.
Proc. Natl. Acad. Sci. USA
86
:
3803
3807
.
36
Major
J.
,
Fletcher
J. E.
,
Hamilton
T. A.
.
2002
.
IL-4 pretreatment selectively enhances cytokine and chemokine production in lipopolysaccharide-stimulated mouse peritoneal macrophages.
J. Immunol.
168
:
2456
2463
.
37
Milner
J. D.
,
Orekov
T.
,
Ward
J. M.
,
Cheng
L.
,
Torres-Velez
F.
,
Junttila
I.
,
Sun
G.
,
Buller
M.
,
Morris
S. C.
,
Finkelman
F. D.
,
Paul
W. E.
.
2010
.
Sustained IL-4 exposure leads to a novel pathway for hemophagocytosis, inflammation, and tissue macrophage accumulation.
Blood
116
:
2476
2483
.
38
Brodie
C.
,
Goldreich
N.
,
Haiman
T.
,
Kazimirsky
G.
.
1998
.
Functional IL-4 receptors on mouse astrocytes: IL-4 inhibits astrocyte activation and induces NGF secretion.
J. Neuroimmunol.
81
:
20
30
.
39
Awatsuji
H.
,
Furukawa
Y.
,
Hirota
M.
,
Murakami
Y.
,
Nii
S.
,
Furukawa
S.
,
Hayashi
K.
.
1993
.
Interleukin-4 and -5 as modulators of nerve growth factor synthesis/secretion in astrocytes.
J. Neurosci. Res.
34
:
539
545
.
40
Gow
D. J.
,
Sester
D. P.
,
Hume
D. A.
.
2010
.
CSF-1, IGF-1, and the control of postnatal growth and development.
J. Leukoc. Biol.
88
:
475
481
.
41
Liu
H.
,
Prayson
R. A.
,
Estes
M. L.
,
Drazba
J. A.
,
Barnett
G. H.
,
Bingaman
W.
,
Liu
J.
,
Jacobs
B. S.
,
Barna
B. P.
.
2000
.
In vivo expression of the interleukin 4 receptor alpha by astrocytes in epilepsy cerebral cortex.
Cytokine
12
:
1656
1661
.
42
Hu
S.
,
Sheng
W. S.
,
Peterson
P. K.
,
Chao
C. C.
.
1995
.
Differential regulation by cytokines of human astrocyte nitric oxide production.
Glia
15
:
491
494
.
43
Pousset
F.
,
Cremona
S.
,
Dantzer
R.
,
Kelley
K.
,
Parnet
P.
.
1999
.
Interleukin-4 and interleukin-10 regulate IL1-beta induced mouse primary astrocyte activation: a comparative study.
Glia
26
:
12
21
.
44
Garg
S. K.
,
Kipnis
J.
,
Banerjee
R.
.
2009
.
IFN-gamma and IL-4 differentially shape metabolic responses and neuroprotective phenotype of astrocytes.
J. Neurochem.
108
:
1155
1166
.
45
Alliot
F.
,
Godin
I.
,
Pessac
B.
.
1999
.
Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain.
Brain Res. Dev. Brain Res.
117
:
145
152
.
46
Mildner
A.
,
Schmidt
H.
,
Nitsche
M.
,
Merkler
D.
,
Hanisch
U. K.
,
Mack
M.
,
Heikenwalder
M.
,
Brück
W.
,
Priller
J.
,
Prinz
M.
.
2007
.
Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions.
Nat. Neurosci.
10
:
1544
1553
.
47
Michelucci
A.
,
Heurtaux
T.
,
Grandbarbe
L.
,
Morga
E.
,
Heuschling
P.
.
2009
.
Characterization of the microglial phenotype under specific pro-inflammatory and anti-inflammatory conditions: Effects of oligomeric and fibrillar amyloid-beta.
J. Neuroimmunol.
210
:
3
12
.
48
Ponomarev
E. D.
,
Maresz
K.
,
Tan
Y.
,
Dittel
B. N.
.
2007
.
CNS-derived interleukin-4 is essential for the regulation of autoimmune inflammation and induces a state of alternative activation in microglial cells.
J. Neurosci
.
27
:
10714
10721
.
49
Chao
C. C.
,
Hu
S.
,
Peterson
P. K.
.
1995
.
Modulation of human microglial cell superoxide production by cytokines.
J. Leukoc. Biol.
58
:
65
70
.
50
Butovsky
O.
,
Talpalar
A. E.
,
Ben-Yaakov
K.
,
Schwartz
M.
.
2005
.
Activation of microglia by aggregated beta-amyloid or lipopolysaccharide impairs MHC-II expression and renders them cytotoxic whereas IFN-gamma and IL-4 render them protective.
Mol. Cell. Neurosci.
29
:
381
393
.
51
Suzumura
A.
,
Sawada
M.
,
Itoh
Y.
,
Marunouchi
T.
.
1994
.
Interleukin-4 induces proliferation and activation of microglia but suppresses their induction of class II major histocompatibility complex antigen expression.
J. Neuroimmunol.
53
:
209
218
.
52
Lyons
A.
,
McQuillan
K.
,
Deighan
B. F.
,
O’Reilly
J. A.
,
Downer
E. J.
,
Murphy
A. C.
,
Watson
M.
,
Piazza
A.
,
O’Connell
F.
,
Griffin
R.
, et al
.
2009
.
Decreased neuronal CD200 expression in IL-4-deficient mice results in increased neuroinflammation in response to lipopolysaccharide.
Brain Behav. Immun.
23
:
1020
1027
.
53
Butovsky
O.
,
Ziv
Y.
,
Schwartz
A.
,
Landa
G.
,
Talpalar
A. E.
,
Pluchino
S.
,
Martino
G.
,
Schwartz
M.
.
2006
.
Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells.
Mol. Cell. Neurosci.
31
:
149
160
.
54
Butovsky
O.
,
Bukshpan
S.
,
Kunis
G.
,
Jung
S.
,
Schwartz
M.
.
2007
.
Microglia can be induced by IFN-gamma or IL-4 to express neural or dendritic-like markers.
Mol. Cell. Neurosci.
35
:
490
500
.
55
Verbitsky
M.
,
Yonan
A. L.
,
Malleret
G.
,
Kandel
E. R.
,
Gilliam
T. C.
,
Pavlidis
P.
.
2004
.
Altered hippocampal transcript profile accompanies an age-related spatial memory deficit in mice.
Learn. Mem.
11
:
253
260
.
56
Zahn
J. M.
,
Poosala
S.
,
Owen
A. B.
,
Ingram
D. K.
,
Lustig
A.
,
Carter
A.
,
Weeraratna
A. T.
,
Taub
D. D.
,
Gorospe
M.
,
Mazan-Mamczarz
K.
, et al
.
2007
.
AGEMAP: a gene expression database for aging in mice.
PLoS Genet.
3
:
e201
.
57
Lynch
M. A.
2010
.
Age-related neuroinflammatory changes negatively impact on neuronal function
.
Front. Aging Neurosci.
1
:
6
.
58
Bellinger
F. P.
,
Madamba
S.
,
Siggins
G. R.
.
1993
.
Interleukin 1 beta inhibits synaptic strength and long-term potentiation in the rat CA1 hippocampus.
Brain Res.
628
:
227
234
.
59
Balschun
D.
,
Wetzel
W.
,
Del Rey
A.
,
Pitossi
F.
,
Schneider
H.
,
Zuschratter
W.
,
Besedovsky
H. O.
.
2004
.
Interleukin-6: a cytokine to forget.
FASEB J.
18
:
1788
1790
.
60
Curran
B.
,
O’Connor
J. J.
.
2001
.
The pro-inflammatory cytokine interleukin-18 impairs long-term potentiation and NMDA receptor-mediated transmission in the rat hippocampus in vitro.
Neuroscience
108
:
83
90
.
61
Maher
F. O.
,
Nolan
Y.
,
Lynch
M. A.
.
2005
.
Downregulation of IL-4-induced signalling in hippocampus contributes to deficits in LTP in the aged rat.
Neurobiol. Aging
26
:
717
728
.
62
Nolan
Y.
,
Maher
F. O.
,
Martin
D. S.
,
Clarke
R. M.
,
Brady
M. T.
,
Bolton
A. E.
,
Mills
K. H.
,
Lynch
M. A.
.
2005
.
Role of interleukin-4 in regulation of age-related inflammatory changes in the hippocampus.
J. Biol. Chem.
280
:
9354
9362
.
63
Fenn
A. M.
,
Henry
C. J.
,
Huang
Y.
,
Dugan
A.
,
Godbout
J. P.
.
2012
.
Lipopolysaccharide-induced interleukin (IL)-4 receptor-α expression and corresponding sensitivity to the M2 promoting effects of IL-4 are impaired in microglia of aged mice.
Brain Behav. Immun.
26
:
766
777
.
64
Griffin
R.
,
Nally
R.
,
Nolan
Y.
,
McCartney
Y.
,
Linden
J.
,
Lynch
M. A.
.
2006
.
The age-related attenuation in long-term potentiation is associated with microglial activation.
J. Neurochem.
99
:
1263
1272
.
65
Kitazawa
M.
,
Cheng
D.
,
Tsukamoto
M. R.
,
Koike
M. A.
,
Wes
P. D.
,
Vasilevko
V.
,
Cribbs
D. H.
,
LaFerla
F. M.
.
2011
.
Blocking IL-1 signaling rescues cognition, attenuates tau pathology, and restores neuronal β-catenin pathway function in an Alzheimer’s disease model.
J. Immunol.
187
:
6539
6549
.
66
Abbas
N.
,
Bednar
I.
,
Mix
E.
,
Marie
S.
,
Paterson
D.
,
Ljungberg
A.
,
Morris
C.
,
Winblad
B.
,
Nordberg
A.
,
Zhu
J.
.
2002
.
Up-regulation of the inflammatory cytokines IFN-γ and IL-12 and down-regulation of IL-4 in cerebral cortex regions of APP(SWE) transgenic mice.
J. Neuroimmunol.
126
:
50
57
.
67
Kiyota
T.
,
Okuyama
S.
,
Swan
R. J.
,
Jacobsen
M. T.
,
Gendelman
H. E.
,
Ikezu
T.
.
2010
.
CNS expression of anti-inflammatory cytokine interleukin-4 attenuates Alzheimer’s disease-like pathogenesis in APP+PS1 bigenic mice.
FASEB J.
24
:
3093
3102
.
68
Jimenez
S.
,
Baglietto-Vargas
D.
,
Caballero
C.
,
Moreno-Gonzalez
I.
,
Torres
M.
,
Sanchez-Varo
R.
,
Ruano
D.
,
Vizuete
M.
,
Gutierrez
A.
,
Vitorica
J.
.
2008
.
Inflammatory response in the hippocampus of PS1M146L/APP751SL mouse model of Alzheimer’s disease: age-dependent switch in the microglial phenotype from alternative to classic.
J. Neurosci.
28
:
11650
11661
.
69
Walker
D. G.
,
Dalsing-Hernandez
J. E.
,
Campbell
N. A.
,
Lue
L.-F.
.
2009
.
Decreased expression of CD200 and CD200 receptor in Alzheimer’s disease: a potential mechanism leading to chronic inflammation.
Exp. Neurol.
215
:
5
19
.
70
Lyons
A.
,
Downer
E. J.
,
Crotty
S.
,
Nolan
Y. M.
,
Mills
K. H.
,
Lynch
M. A.
.
2007
.
CD200 ligand receptor interaction modulates microglial activation in vivo and in vitro: a role for IL-4.
J. Neurosci.
27
:
8309
8313
.
71
Koning
N.
,
van Eijk
M.
,
Pouwels
W.
,
Brouwer
M. S.
,
Voehringer
D.
,
Huitinga
I.
,
Hoek
R. M.
,
Raes
G.
,
Hamann
J.
.
2010
.
Expression of the inhibitory CD200 receptor is associated with alternative macrophage activation.
J. Innate Immun.
2
:
195
200
.
72
Shimizu
E.
,
Kawahara
K.
,
Kajizono
M.
,
Sawada
M.
,
Nakayama
H.
.
2008
.
IL-4-induced selective clearance of oligomeric beta-amyloid peptide(1-42) by rat primary type 2 microglia.
J. Immunol.
181
:
6503
6513
.
73
Yamamoto
M.
,
Kiyota
T.
,
Walsh
S. M.
,
Liu
J.
,
Kipnis
J.
,
Ikezu
T.
.
2008
.
Cytokine-mediated inhibition of fibrillar amyloid-beta peptide degradation by human mononuclear phagocytes.
J. Immunol.
181
:
3877
3886
.
74
Cao
C.
,
Arendash
G. W.
,
Dickson
A.
,
Mamcarz
M. B.
,
Lin
X.
,
Ethell
D. W.
.
2009
.
Abeta-specific Th2 cells provide cognitive and pathological benefits to Alzheimer’s mice without infiltrating the CNS.
Neurobiol. Dis.
34
:
63
70
.
75
Falcone
M.
,
Rajan
A. J.
,
Bloom
B. R.
,
Brosnan
C. F.
.
1998
.
A critical role for IL-4 in regulating disease severity in experimental allergic encephalomyelitis as demonstrated in IL-4-deficient C57BL/6 mice and BALB/c mice.
J. Immunol.
160
:
4822
4830
.
76
Hulshof
S.
,
Montagne
L.
,
De Groot
C. J.
,
Van Der Valk
P.
.
2002
.
Cellular localization and expression patterns of interleukin-10, interleukin-4, and their receptors in multiple sclerosis lesions.
Glia
38
:
24
35
.
77
Mikita
J.
,
Dubourdieu-Cassagno
N.
,
Deloire
M. S.
,
Vekris
A.
,
Biran
M.
,
Raffard
G.
,
Brochet
B.
,
Canron
M.-H.
,
Franconi
J.-M.
,
Boiziau
C.
,
Petry
K. G.
.
2011
.
Altered M1/M2 activation patterns of monocytes in severe relapsing experimental rat model of multiple sclerosis. Amelioration of clinical status by M2 activated monocyte administration
.
Mult. Scler.
17
:
2
15
.
78
Butovsky
O.
,
Landa
G.
,
Kunis
G.
,
Ziv
Y.
,
Avidan
H.
,
Greenberg
N.
,
Schwartz
A.
,
Smirnov
I.
,
Pollack
A.
,
Jung
S.
,
Schwartz
M.
.
2006
.
Induction and blockage of oligodendrogenesis by differently activated microglia in an animal model of multiple sclerosis.
J. Clin. Invest.
116
:
905
915
.
79
Qin
H.
,
Yeh
W. I.
,
De Sarno
P.
,
Holdbrooks
A. T.
,
Liu
Y.
,
Muldowney
M. T.
,
Reynolds
S. L.
,
Yanagisawa
L. L.
,
Fox
T. H.
 III
,
Park
K.
, et al
.
2012
.
Signal transducer and activator of transcription-3/suppressor of cytokine signaling-3 (STAT3/SOCS3) axis in myeloid cells regulates neuroinflammation.
Proc. Natl. Acad. Sci. USA
109
:
5004
5009
.
80
Bondy
M. L.
,
Scheurer
M. E.
,
Malmer
B.
,
Barnholtz-Sloan
J. S.
,
Davis
F. G.
,
Il’yasova
D.
,
Kruchko
C.
,
McCarthy
B. J.
,
Rajaraman
P.
,
Schwartzbaum
J. A.
, et al
Brain Tumor Epidemiology Consortium
.
2008
.
Brain tumor epidemiology: consensus from the Brain Tumor Epidemiology Consortium.
Cancer
113
(
7
Suppl.
):
1953
1968
.
81
Olver
S.
,
Apte
S.
,
Baz
A.
,
Kienzle
N.
.
2007
.
The duplicitous effects of interleukin 4 on tumour immunity: how can the same cytokine improve or impair control of tumour growth?
Tissue Antigens
69
:
293
298
.
82
Debinski
W.
,
Gibo
D. M.
.
2000
.
Molecular expression analysis of restrictive receptor for interleukin 13, a brain tumor-associated cancer/testis antigen.
Mol. Med.
6
:
440
449
.
83
Puri
R. K.
,
Leland
P.
,
Kreitman
R. J.
,
Pastan
I.
.
1994
.
Human neurological cancer cells express interleukin-4 (IL-4) receptors which are targets for the toxic effects of IL4-Pseudomonas exotoxin chimeric protein.
Int. J. Cancer
58
:
574
581
.
84
Joshi
B. H.
,
Leland
P.
,
Asher
A.
,
Prayson
R. A.
,
Varricchio
F.
,
Puri
R. K.
.
2001
.
In situ expression of interleukin-4 (IL-4) receptors in human brain tumors and cytotoxicity of a recombinant IL-4 cytotoxin in primary glioblastoma cell cultures.
Cancer Res.
61
:
8058
8061
.
85
Brenner
A. V.
,
Linet
M. S.
,
Fine
H. A.
,
Shapiro
W. R.
,
Selker
R. G.
,
Black
P. M.
,
Inskip
P. D.
.
2002
.
History of allergies and autoimmune diseases and risk of brain tumors in adults.
Int. J. Cancer
99
:
252
259
.
86
Wiemels
J. L.
,
Wiencke
J. K.
,
Sison
J. D.
,
Miike
R.
,
McMillan
A.
,
Wrensch
M.
.
2002
.
History of allergies among adults with glioma and controls.
Int. J. Cancer
98
:
609
615
.
87
Schwartzbaum
J.
,
Ahlbom
A.
,
Malmer
B.
,
Lönn
S.
,
Brookes
A. J.
,
Doss
H.
,
Debinski
W.
,
Henriksson
R.
,
Feychting
M.
.
2005
.
Polymorphisms associated with asthma are inversely related to glioblastoma multiforme.
Cancer Res.
65
:
6459
6465
.
88
Ruan
Z.
,
Zhao
Y.
,
Yan
L.
,
Chen
H.
,
Fan
W.
,
Chen
J.
,
Wu
Q.
,
Qian
J.
,
Zhang
T.
,
Zhou
K.
, et al
.
2011
.
Single nucleotide polymorphisms in IL-4Ra, IL-13 and STAT6 genes occurs in brain glioma.
Front Biosci (Elite Ed)
3
:
33
45
.
89
Scheurer
M. E.
,
Amirian
E.
,
Cao
Y.
,
Gilbert
M. R.
,
Aldape
K. D.
,
Kornguth
D. G.
,
El-Zein
R.
,
Bondy
M. L.
.
2008
.
Polymorphisms in the interleukin-4 receptor gene are associated with better survival in patients with glioblastoma
.
Clin. Cancer Res
.
14
:
6640
6646
.
90
Saleh
M.
,
Davis
I. D.
,
Wilks
A. F.
.
1997
.
The paracrine role of tumour-derived mIL-4 on tumour-associated endothelium.
Int. J. Cancer
72
:
664
672
.
91
Topp
M. S.
,
Papadimitriou
C. A.
,
Eitelbach
F.
,
Koenigsmann
M.
,
Oelmann
E.
,
Koehler
B.
,
Oberberg
D.
,
Reufi
B.
,
Stein
H.
,
Thiel
E.
, et al
.
1995
.
Recombinant human interleukin 4 has antiproliferative activity on human tumor cell lines derived from epithelial and nonepithelial histologies.
Cancer Res.
55
:
2173
2176
.
92
Benedetti
S.
,
Bruzzone
M. G.
,
Pollo
B.
,
DiMeco
F.
,
Magrassi
L.
,
Pirola
B.
,
Cirenei
N.
,
Colombo
M. P.
,
Finocchiaro
G.
.
1999
.
Eradication of rat malignant gliomas by retroviral-mediated, in vivo delivery of the interleukin 4 gene.
Cancer Res.
59
:
645
652
.
93
Post
D. E.
,
Sandberg
E. M.
,
Kyle
M. M.
,
Devi
N. S.
,
Brat
D. J.
,
Xu
Z.
,
Tighiouart
M.
,
Van Meir
E. G.
.
2007
.
Targeted cancer gene therapy using a hypoxia inducible factor dependent oncolytic adenovirus armed with interleukin-4.
Cancer Res.
67
:
6872
6881
.
94
Cherry
T.
,
Longo
S. L.
,
Tovar-Spinoza
Z.
,
Post
D. E.
.
2010
.
Second-generation HIF-activated oncolytic adenoviruses with improved replication, oncolytic, and antitumor efficacy.
Gene Ther.
17
:
1430
1441
.
95
Volpert
O. V.
,
Fong
T.
,
Koch
A. E.
,
Peterson
J. D.
,
Waltenbaugh
C.
,
Tepper
R. I.
,
Bouck
N. P.
.
1998
.
Inhibition of angiogenesis by interleukin 4.
J. Exp. Med.
188
:
1039
1046
.
96
Tepper
R. I.
,
Coffman
R. L.
,
Leder
P.
.
1992
.
An eosinophil-dependent mechanism for the antitumor effect of interleukin-4.
Science
257
:
548
551
.
97
Curran
C. S.
,
Bertics
P. J.
.
2012
.
Eosinophils in glioblastoma biology.
J. Neuroinflammation
9
:
11
.
98
Gocheva
V.
,
Wang
H.-W.
,
Gadea
B. B.
,
Shree
T.
,
Hunter
K. E.
,
Garfall
A. L.
,
Berman
T.
,
Joyce
J. A.
.
2010
.
IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion.
Genes Dev.
24
:
241
255
.
99
Mantovani
A.
,
Sica
A.
.
2010
.
Macrophages, innate immunity and cancer: balance, tolerance, and diversity.
Curr. Opin. Immunol.
22
:
231
237
.
100
Linde
N.
,
Lederle
W.
,
Depner
S.
,
van Rooijen
N.
,
Gutschalk
C. M.
,
Mueller
M. M.
.
2012
.
Vascular endothelial growth factor-induced skin carcinogenesis depends on recruitment and alternative activation of macrophages.
J. Pathol.
227
:
17
28
.
101
Stellwagen
D.
,
Malenka
R. C.
.
2006
.
Synaptic scaling mediated by glial TNF-alpha.
Nature
440
:
1054
1059
.
102
Balschun
D.
,
Wetzel
W.
,
Del Rey
A.
,
Pitossi
F.
,
Schneider
H.
,
Zuschratter
W.
,
Besedovsky
H. O.
.
2004
.
Interleukin-6: a cytokine to forget.
FASEB J.
18
:
1788
1790
.
103
Derecki
N. C.
,
Cronk
J. C.
,
Lu
Z.
,
Xu
E.
,
Abbott
S. B.
,
Guyenet
P. G.
,
Kipnis
J.
.
2012
.
Wild-type microglia arrest pathology in a mouse model of Rett syndrome.
Nature
484
:
105
109
.

The authors have no financial conflicts of interest.