Oncostatin M Receptor-β Signaling Limits Monocytic Cell Recruitment in Acute Inflammation¹

Cytokine responses elicited via the ubiquitously expressed signal-transducing receptor gp130 have been implicated in both immune regulation and homeostasis (1). In this respect, gp130 acts as the β-signaling subunit for a family of cytokines including IL-6, IL-11, IL-27, oncostatin M (OSM),³ LIF, ciliary neurotrophic factor, cardiotrophin-1, cardiotrophin-like cytokine, and neuropoietin (2, 3). Activation of gp130 by these cytokines occurs through various mechanisms. IL-6, IL-11, and IL-27 activate gp130 after binding to specific nonsignaling receptor subunits, which then trigger the homodimerization and activation of gp130. In contrast, cytokines including LIF and OSM engage gp130 to form a heterodimer interaction with one of two gp130-related proteins, LIFR or OSMRβ. These distinct modes of gp130 activation may provide a molecular basis for the pattern of cellular events orchestrated by these related factors (2). In this communication, we have used OSMRβ-deficient (OSMR-knockout; KO) mice to examine OSMRβ signaling during acute inflammation.

In vitro studies have highlighted functions for OSM in stromal cell activation, leukocyte recruitment, and tissue injury (4, 5, 6, 7, 8, 9). In many instances, these OSM activities closely relate to those associated with the archetypal gp130-activating cytokine IL-6. Ultimately, these reports infer that both factors orchestrate pro- and anti-inflammatory responses. However, it would be expected that gp130 homodimer activation would elicit biological outcomes distinct from those governed by activation of a gp130:OSMRβ heterodimer. Such differences are clearly evident in the control of hemopoiesis by gp130-related cytokines, whereby the alterations in hematological characteristics seen in OSMR-KO mice are very much distinct from those described for LIFR-KO, IL-11R-KO, and IL-6-KO mice (10, 11, 12, 13, 14). Such differences are not, however, well defined during inflammation. Although in vitro studies have identified a number of inflammatory events regulated by OSM, these activities are often indistinguishable from those controlled by IL-6 (7, 15, 16, 17, 18). Indeed, studies using experimental models of arthritis illustrate that although IL-6KO mice remain resistant to arthritis, OSMR-KO mice develop disease hallmarks that are comparable with those seen in wild-type (WT) mice (19). Consequently, it remains to be established whether OSM and IL-6 elicit distinct inflammatory processes in vivo or whether their control of common biological activities provides a cytokine hierarchy with one factor overriding the properties of the other.

In vitro studies illustrate that OSM and IL-6 share a similar capacity to control the differential expression of certain inflammatory chemokines (7, 15, 16, 17, 20, 21). Investigations with IL-6-KO mice have shown that the IL-6 control of these processes is pivotal for the successful resolution of neutrophil infiltration and the development of acquired immunity through increased T cell recruitment (22, 23, 24). The contribution of OSMRβ signaling to the control of this immunological switch has not, however, been examined. In this study, we show that under conditions of acute inflammatory challenge, mice deficient in OSMRβ show increased monocyte recruitment, but no alteration in neutrophil and lymphocyte migration. These findings emphasize a selective role of OSMRβ signaling in regulating monocytic cell infiltration, and highlight a critical in vivo difference between gp130 signaling via IL-6R and OSMRβ during inflammation.

Chemicals were purchased from Sigma-Aldrich unless otherwise stated. Human recombinant OSM, IL-1β, and IFN-γ were from R&D Systems. Cell culture reagents were from Invitrogen. Directly conjugated Abs against human LIFRβ, gp130, CD14, CD3, CD4, and CXCR1 were from BD Pharmingen, whereas the anti-human OSMRβ Ab (AN-A2) was from Santa Cruz Biotechnology. Fluorochrome-conjugated Abs against murine CD3, CD4, and CCR5 were from BD Pharmingen, and F4/80 was purchased from Serotec. Ficoll-Paque was from Amersham Biosciences.

Venous blood from healthy individuals was mixed with an equal volume of 2% (w/v) dextran, 0.8% (w/v) trisodium citrate in PBS (pH 7.4) to allow erythrocyte sedimentation. Plasma was collected and layered on Ficoll (2:1 (v/v) plasma-Ficoll) before centrifugation at 20°C for 35 min at 400 × g. The PBMC interface was collected and washed with PBS to remove platelet contamination. Cells were either directly analyzed by flow cytometry or resuspended in serum-free RPMI 1640 containing 2 mM l-glutamine, 100U/ml penicillin, and 100 μg/ml streptomycin. The neutrophil pellet was collected, and contaminating erythrocytes were removed by hypotonic lysis before analysis by flow cytometry.

Human peritoneal mesothelial cells (HPMC) were cultured as previously described from trypsin-digested omental tissue in accordance with ethical approval from the Bro Taf Health Authority (25). Cell cultures were established in Earle’s buffered 199 medium containing 10% FCS, 2 mM l-glutamine, 100 U/ml penicillin, 100 μg/ml streptomycin, 5 μg/ml transferrin, 5 μg/ml insulin, and 0.4 μg/ml hydrocortisone at 37°C and 5% CO₂. Experiments were performed on isolates no older than the second passage.

PBMC (2 × 10⁶ cells/ml) were stimulated overnight at 37°C under serum-free conditions with defined concentrations of OSM and IL-1β. Optimal IL-1β concentrations were based on the levels quantified in vivo and were shown to elicit robust chemokine induction in vitro. HPMC monolayers were growth arrested for 48 h in the absence of FCS before stimulation at 37°C as indicated. Culture supernatants were rendered cell free by centrifugation and stored at −70°C.

OSMR-KO mice were generated as previously described (13). Experiments were performed under Home Office License PPL-30/2269 on 6- to 12-wk-old C57/BL6 WT, IL-6-KO, and OSMR-KO mice.

A cell-free supernatant was prepared from SES (22). The SES-induced secretion of murine IL-6 from macrophage RAW-264 cells was used to standardize the potency of SES batches. Peritoneal inflammation was induced by intraperitoneal i.p. administration of SES (500 μl). At intervals, mice were sacrificed, and the peritoneal cavity was lavaged with 2 ml of ice cold PBS. Leukocyte infiltration was analyzed by differential cell counting and flow cytometry after staining with Abs against pan leukocyte markers. Inflammatory mediator concentrations were quantified using commercial ELISA kits.

Human OSMRβ, LIFRβ, IL-6R, and gp130 was detected by flow cytometry (FACSCalibur; BD Biosciences) using PE-conjugated Abs against the extracellular portion of these receptors (16, 17). To assign gp130 and OSMRβ expression to individual leukocyte subpopulations, dual Ab labeling was performed using Abs against CXCR1 (neutrophils), CD14 (monocytes), and CD3 (T-lymphocytes). Data were acquired from 10,000 events for HPMC and 50,000 events for leukocytes. Monocytic subsets were gated using a FITC-conjugated anti-F4/80 Ab in combination with an allophycocyanin-conjugated anti-CD11b Ab, and CCR5 expression evaluated using a PE-conjugated anti-CCR5 Ab.

Human CCL2, CXCL8, CXCL9, and CXCL10 and murine CCL2 and IL-6 were quantified using OptEIA kits from BD Biosciences. Human IL-6, CCL5, and CXCL11, and murine CCL3, CCL4, and CCL5 production were determined using matched ELISA Duosets from R&D Systems. Murine OSM concentrations were quantified using an ELISA system developed using 0.8 μg/ml goat anti-mouse OSM polyclonal IgG (AF-495-NA; R&D Systems) as a capture Ab and 200 ng/ml biotinylated goat anti-mouse OSM polyclonal IgG (BAF495; R&D Systems) as a secondary Ab. Immunodetection was monitored using streptavidin-HRP (R&D Systems) and Sureblue TMB substrate (KPL). Concentrations of OSM were quantified against murine OSM (495-MO-025; R&D Systems) as a protein standard.

Total RNA was extracted from HPMC and monocytic THP-1 cells using TRI reagent (Sigma-Aldrich). cDNA was reverse transcribed from 1 μg of total RNA using Superscript II RNase H⁻ RT (Invitrogen) and random hexamers (100 μM) from Amersham Biosciences. PCR was performed with primers for GAPDH (sense, 5′-CGAGATCCCTCCAAAATCAA-3′; anti-sense, 5′-ATCCACAGTCTTCTGGGTGG-3′) and IL-31R (sense, 5′-TGGTGGAGGCCTTCTTATTC-3′; anti-sense, 5′-CACAGAGTCATCAGACTCCTTCA-3′). A denaturation step of 94°C for 2 min was followed by 32 cycles comprising 30 s at 94°C, 30 s at 65°C, and 90 s at 72°C and a final extension step of 15 min at 72°C. Products were analyzed by electrophoresis on a 2% (w/v) agarose gel and visualized with ethidium bromide staining.

Nuclear extracts were prepared from HPMC as previously described (16). EMSAs using [α-³²P]dTTP labeled oligonucleotides containing a DNA consensus motif for NF-κB binding (5′-gaTCCATGGGGAATTCCCC-3′ and 3′-AGGTACCCCTTAAGGGGag-5′) was performed with 3 μg of nuclear extract. Rabbit polyclonal Abs against NF-κB-p50 (sc-7178), -p65 (sc-109), -p52, and c-Rel (Santa Cruz Biotechnology) were used in supershift analysis. Quantification of banding intensity was performed for each time interval using the Bio-Rad gel documentation system and QuanityOne software. For HPMC stimulations, temporal changes in IL-1β-mediated NF-κB activation following OSM costimulation is expressed as a ratio of the banding intensity observed with IL-1β alone. In vivo NF-κB activation in OSMR-KO or IL-6KO mice was expressed as a ratio of the banding intensity seen in WT mice at each time point. Data were acquired from a total of three independent experiments.

Statistical analyses were performed using Student’s t test. A p value of <0.05 was considered significant. All data represent mean ± SEM.

To examine the role of OSMRβ signaling during acute inflammation, studies were done with the SES-mediated model of peritoneal inflammation (17, 22, 23). As shown in Fig. 1,A, administration (i.p.) of SES led to an initial influx of neutrophils that were subsequently removed and replaced by a more sustained population of mononuclear cells. Comparative analysis in WT and OSMR-KO mice, however, emphasized that an absence in OSMRβ signaling capacity led to a significant increase in monocytic cell trafficking to the peritoneal cavity. To substantiate this observation, flow cytometry was used to monitor SES-induced changes in F4/80⁺CD11b⁺ cell trafficking (Fig. 1,B). Such analysis identifies two distinct populations defined as resident-like F4/80^highCD11b^high monocytic cells and infiltrating F4/80^lowCD11b⁺ monocytic cells, which emerge following inflammatory activation (26). Before SES activation, the resident monocytic population was predominantly F4/80^highCD11b^high. However, consistent with initial reports into the inflammatory trafficking of leukocytes within pleural cavities (27), SES stimulation triggered an early exodus of these cells from the peritoneal cavity, together with a marked influx of F4/80^lowCD11b⁺ monocytic cells. However, as inflammation progressed (24 h), flow cytometry affirmed the re-emergence of a resident-like F4/80^highCD11b^high population (Fig. 1,B). Although this profile of monocytic cell emigration and recruitment was still evident in OSMR-KO mice, the proportion of infiltrating F4/80^lowCD11b⁺ monocytic cells was elevated as compared with that of WT mice (Fig. 1 B).

In contrast, both neutrophil and lymphocyte recruitment remained unaffected by the absence of OSMRβ (Fig. 1,A). This response is distinct from that exhibited by IL-6-KO mice, which as previously reported display enhanced neutrophil migration but no change in monocytic cell recruitment following SES activation (Fig. 1,C) (22, 23). The increase in monocytic cell infiltration seen in OSMR-KO mice was not however attributable to alterations in the number of circulating monocytic cells (Fig. 1 D), suggesting that OSMRβ signaling selectively influences monocytic cell recruitment during acute inflammation. These data endorse a hitherto unidentified difference between IL-6 and OSM signaling.

To establish a basis for this difference in monocytic cell trafficking, initial studies profiled OSMRβ expression on HPMC and leukocyte subsets. These results illustrate that OSMRβ expression is confined to HPMC. In addition, HPMC were found to lack LIFR expression and therefore respond to OSM only via OSMRβ:gp130 heterodimer (data not shown; see also Ref. 16). Mesothelial cells represent the principle cell type lining the peritoneum and represent the major source of inflammatory chemokines within the peritoneal cavity (25, 28). In vitro stimulation of HPMC with OSM significantly promoted expression of CCL2, but not CCL3, CCL5, and CXCL8 (Fig. 2 A), and had a minimal affect on the T cell chemoattractants CXCL9, CXCL10, and CXCL11 (not shown).

To fully appreciate the contribution of OSMRβ signaling to the chemokine network within the peritoneal cavity it was important to consider the role of IL-31, which utilizes OSMRβ as a β-signaling subunit following binding to a cognate IL-31 receptor (IL-31Rα; Ref. 29). Stimulation of HPMC with IL-31 had no effect on CCL2 expression (Fig. 2,B), whereas RT-PCR analysis of HPMC-derived cDNA confirmed a lack of IL-31Rα expression (Fig. 2 C).

As previously described for IL-6, OSM differentially affects inflammatory chemokine expression and selectively inhibits the IL-1β-mediated suppression of CXCL8 by HPMC (17, 22). In contrast to IL-6, however, OSM also impaired the IL-1β induction of CCL5 (Fig. 3). These data strengthen the case for the involvement of OSM in governing monocytic cell recruitment.

In vitro studies presented herein, and based collectively on other reports, present an overall view that IL-6 and OSM are comparable in their ability to govern chemokine expression, which does not account for the difference in inflammatory cell trafficking observed between OSMR-KO and IL-6KO mice (Fig. 1). The notable difference is the manner by which OSM and IL-6 affect CCL5 expression. Consequently, OSM and IL-6 may individually affect the in vivo expression of certain inflammatory chemokines, whereas the common induction of chemokines including CCL2 might be preferentially controlled by one overarching factor. To evaluate this assertion, studies first examined changes in the temporal expression of IL-1β and IL-6 following SES activation in WT and OSMR-KO mice (Fig. 4,A). These data highlight that two principle regulators of inflammatory chemokines in vivo remain unaffected by an absence in OSMRβ signaling. Indeed, in vitro analysis of OSM-stimulated HPMC confirmed that IL-6 expression was unaffected by OSM (Fig. 4,B). In line with the early temporal induction of both IL-6 and IL-1β, OSM concentrations following SES stimulation also increased markedly in both WT and OSMR-KO mice during the initial part of the inflammatory response (Fig. 4,A). However the kinetics of OSM production was more sustained than that of IL-6 and IL-1β (Fig. 4 A).

To evaluate the contribution of OSMRβ signaling to the in vivo control of inflammatory chemokines, CCL2 and the CCR5 ligands CCL3, CCL4, and CCL5 were quantified after SES stimulation. Although OSM was found to induce human CCL2 in vitro (Fig. 2), the profile of murine CCL2 expression, and that of CCL3 and CCL4, observed in OSMR-KO mice, remained consistent with that seen in WT mice (Fig. 5,A). In contrast, CCL5 levels were significantly elevated in SES challenged OSMR-KO mice (Fig. 5,A). To substantiate these observations, SES-induced changes in CCL2 and CCL5 were monitored in IL-6KO mice. In this respect, CCL2 and CCL5 levels were found to be significantly impaired in IL-6KO mice (Fig. 5,B). Consequently, IL-6 appears to predominantly influence CCL2 expression, while OSM may have a greater bearing on CCL5-mediated recruitment. To determine whether the alteration in CCL5 equates to changes in CCR5 expression flow cytometry was used to examine the affect OSMRβ-deficiency had on this inflammatory chemokine receptor. Before SES activation resident peritoneal F4/80^highCD11b⁺ cells could be clustered as either CCR5^low or CCR5^null (Fig. 5,C). However, following SES activation, CCR5 expression within the F4/80⁺CD11b⁺ gate was increased to become homogeneously distributed, suggesting an activation-induced expression of CCR5. No difference was, however, observed between WT and OSMR-KO mice (Fig. 5 C).

The inhibition of IL-1β-driven CCL5 expression by OSM (Fig. 3) infers that OSMRβ signaling may affect NF-κB activity. To test this assertion, EMSAs were performed using a consensus oligonucleotide for NF-κB binding and the banding intensity from all independent experiments quantified by densitometry as described in Materials and Methods (Fig. 6). Analysis of nuclear extracts from HPMC stimulated in vitro with IL-1β and OSM showed that OSM suppresses the IL-1β-mediated activation of NF-κB (Fig. 6,A). Stimulation of HPMC with OSM alone did not promote NF-κB activation (Fig. 6,A). Supershift analysis of the protein-DNA complex from IL-1β-stimulated cells confirmed a classical activation of NF-κB with evidence of both p50 and p65 subunits (Fig. 6,B). The OSM-mediated suppression of NF-κB activation was not however specific for an individual subunit, but globally affected both p50 and p65 (Fig. 6,B). Parallel control EMSA confirmed that IL-1β had no effect on the OSM induction of STAT signaling (data not shown). OSM-mediated control of NF-κB was subsequently confirmed in vivo. In this respect, temporal analysis of SES-triggered NF-κB activation confirmed that nuclear extracts derived from peritoneal membranes of OSMR-KO mice had markedly more enhanced NF-κB activity than WT controls (Fig. 6,C). Analysis of NF-κB activation in peritoneal membranes from SES challenged IL-6-KO mice reaffirmed the specificity of the enhanced NF-κB response displayed by OSMR-KO mice. These data highlight that NF-κB activation is not affected by IL-6 deficiency (Fig. 6,C). Subsequent supershift analysis confirmed a subunit composition similar to that seen in human samples (Fig. 6, B and D). Consequently, a signaling interplay between OSM and NF-κB may affect the regulation of acute inflammation.

Clinical studies and investigations designed to delineate the in vitro properties of OSM emphasis this gp130-activating cytokine can affect many biological activities associated with inflammation, hemopoiesis and development (4, 5, 6, 7, 8, 9, 13, 16, 18, 20, 21). Studies outlined herein offer the first in vivo evaluation of OSM activity during acute inflammation, and demonstrates that OSMRβ signaling selectively affects the inflammatory trafficking of monocytic cells. This response is distinct from the action of IL-6, which predominantly impacts the recruitment and clearance of neutrophils and T cells (22, 23, 24). Such findings highlight that differential activation of a gp130 homodimer complex elicits inflammatory outcomes distinct from that governed by a gp130-OSMRβ heterodimer receptor. Indeed, through comparative analysis of inflammatory events triggered in OSMR-KO and IL-6-KO mice, it is evident that certain genes commonly induced in vitro by both IL-6 and OSM are preferentially regulated in vivo by one prevailing factor. In this respect, IL-6 is a more prominent regulator of CCL2 in vivo than OSM.

The model of acute peritoneal inflammation adopted in this study is designed to profile episodes of bacterial peritonitis typically associated with treatment cessation in end-stage renal failure patients undergoing peritoneal dialysis (28, 30). As with other acute inflammatory diseases, the profile of leukocyte recruitment encountered during peritoneal infection is critical to the outcome of the condition. In this respect, resolution of inflammation is reliant on a successful transition from innate to acquired immunity, which is based on a temporal switch from an initial influx of neutrophils to a more sustained population of mononuclear cells (28). We have previously shown that IL-6 governs this process by differentially affecting both leukocyte apoptosis and chemokine-mediated leukocyte recruitment (22, 24). Subsequent in vitro studies based on this inflammatory context suggested that OSM might serve a similar regulatory role (18). In this respect, analysis of effluent from peritoneal dialysis patients with clinical peritonitis showed a transient increase in OSM concentration within the first 24 h of infection (18). These acute changes in peritoneal OSM correlated with neutrophil infiltration and reports on bacterial peritonitis and acute lung injury have defined neutrophils as the primary source of OSM (18, 31). In this respect, we noted that murine OSM levels were elevated early following SES activation, and coincided with the initial influx of neutrophils. However in progressive chronic conditions OSM concentrations are more sustained and originate from activated macrophages and T lymphocytes (7, 9). Such differences in OSM expression may have a considerable bearing on the inflammatory response since OSM synergizes with other inflammatory mediators including IL-1, TNF-α, IL-6, IL-17, and IFN-γ to affect degradation of extracellular matrix, leukocyte recruitment, and wound healing (16, 20, 21, 32, 33). However, based on OSM reconstitution studies in experimental models of disease, it is difficult to gauge whether OSM directs a protective or detrimental outcome in vivo (5, 6, 9, 34, 35). Consequently, the application of OSMR-KO mice as outlined in this present communication helps to define the inflammatory contribution of OSM and IL-31 to disease progression. In this respect, we found no evidence for an involvement of IL-31 in the in vitro control of chemokine-directed leukocyte trafficking. However, because factors including IFN-γ induce IL-31Rα expression, IL-31 may serve an additional role in more progressive forms of disease (36).

Previous in vitro studies have demonstrated that IL-6 or OSM can regulate chemokine expression in a variety of stromal cells. In many instances, these two gp130-activating cytokines are similar in their capacity to control these inflammatory regulators (7, 15, 16, 17, 20, 21). However, our comparative studies in both IL-6-KO and OSMR-KO mice show that IL-6R and OSMRβ signaling influence distinct aspects of the inflammatory response to affect the profile of leukocyte recruitment. In this respect, IL-6 may override that of OSM to preferentially promote neutrophil clearance and T cell attraction, whereas OSMRβ signaling selectively impairs monocytic cell recruitment. Such restricted control of monocytic cells by OSMRβ may have a considerable bearing on disease outcome and inflammatory resolution, because monocytic cells are critical for the clearance of apoptotic neutrophils and for orchestrating the development of an adaptive immune response (37).

The OSMRβ-mediated control of monocytic cell trafficking centers around a difference in ability of OSM to suppress the IL-1β induced expression of CCL5. This activity is in direct contrast to that of IL-6, which does not regulate CCL5 expression in a similar fashion but seems to be the principle gp130-activating cytokine involved in governing CCL2. This distinction is also evident in vivo where OSMR-KO mice display a heightened and extended profile of CCL5 production as compared with WT and IL-6-KO mice. The link between the regulation of CCL2 and CCL5 is intriguing given that IL-6-KO mice show no significant alteration in monocytic recruitment from that of WT mice. Such findings may highlight functional differences between the gp130-mediated control of CCL2 and CCL5. Our findings infer a potential link between CCL5 and the OSM regulation of mononuclear cell trafficking. However, without a fuller evaluation of other inflammatory chemokines and adhesion molecules potentially involved in governing monocytic cell recruitment it is difficult to gauge whether OSM regulation of CCL5 represents the primary mechanism orchestrating the OSMRβ-mediated control of monocytic cells. Future studies must therefore ascertain the mechanism of this response, but at present this is somewhat restricted by the lack of suitable blocking agents for murine OSM or OSMRβ. It is, however, our contention that CCL5 represents an integral component of this mechanism. Valuable clues relating to this notion are derived from studies relating to cellular changes in the expression of inflammatory chemokine receptors known to bind CCL2 and CCL5. Monocytic CCR2 expression for instance defines a population actively recruited to sites of inflammation, whereas terminal macrophage differentiation leads to a loss in CCR2 expression and an increase in CCR1 and CCR5 (38, 39). In this respect, gp130-mediated signaling from IL-6, LIF, and OSM has been shown to affect various aspects of monocyte differentiation, including macrophage formation, induction of receptors for G-CSF and GM-CSF, and the expansion and phenotypic characteristics of dendritic cells (40, 41, 42, 43, 44). These activities are not, however, universally regulated by all three gp130-activating cytokines (40), suggesting that the OSMRβ control of monocytic cell trafficking may be unique because LIF is not expressed locally during clinical peritonitis (16).

Studies outlined herein infer that monocytic cell trafficking may rely on the ability of OSM to modify NF-κB signaling. In vitro studies endorse the overall view that OSM suppresses expression of certain inflammatory chemokines through inhibition of NF-κB activation. The potential interplay between OSMRβ signaling and NF-κB activity is reiterated in vivo where activation of OSMR-KO mice with SES led to an enhanced temporal activation of NF-κB as compared with WT mice. Supershift analyses suggest that OSM globally knocks down both p50 and p65 subunits. Mechanistically, it is unclear whether this response results from cooperative manipulation of NF-κB signaling, competition for DNA binding within overlapping consensus sites for NF-κB and STAT factors, or NF-κB regulation via cytokine-mediated increases in unphosphorylated STAT3, all of which have been implicated in the gp130 control of NF-κB-mediated events (45, 46, 47). Such interactions are therefore highly complex, and any one of these pathways may lead to a unique set of transcriptional outcomes. It is evident from our comparative studies with both IL-6-KO and OSMR-KO mice that activation of a gp130:OSMRβ heterodimer receptor triggers a series of signaling event affecting NF-κB activation that are not regulated by a receptor consisting of a gp130 homodimer. Further transcriptional studies using suitable reporter assays are therefore required to fully define the nature of this interaction.

In conclusion, the findings presented herein go some way to defining an important difference between IL-6R and OSMRβ signaling during acute inflammation. These studies suggest that while IL-6 critically governs the pattern of neutrophil and T cell recruitment, monocyte trafficking is coordinated by OSM/OSMRβ. The next question is to gauge how control of these acute activities becomes modified in chronic disease. Such insight may have direct bearing on the potential of targeting OSMRβ signaling therapeutically.

The authors have no financial conflict of interest.