Age-related increased prevalence of asthma and nasal polyps in chronic rhinosinusitis and its association with altered IL-6 trans-signaling.

We report that S100 proteins were reduced in patients with chronic rhinosinusitis (CRS). S100A8/9, which is important in epithelial barrier function, was particularly decreased in elderly patients with CRS. Epithelial expression of S100A8/9 is partly regulated by the IL-6 trans-signaling pathway. The goal of this study was to investigate whether or not age-related reduction of S100A8/9 in CRS is associated with blunting of IL-6 trans-signaling. The levels of IL-6, soluble IL-6 receptor (sIL-6R), soluble gp130 (sgp130), and S100A8/9 from control subjects (n = 10), and patients with CRS without nasal polyps (n = 13) and those with CRS with nasal polyps (CRSwNP) (n = 14), were measured by ELISA. Age-related differences in the level of each protein were investigated. Normal human bronchial epithelial cells were cultured in air-liquid interface and stimulated with IL-6/sIL-6R and tumor necrosis factor (TNF)-α with or without the addition of sgp130, a natural inhibitor of IL-6 trans-signaling. There was a significant age-related decline in S100A8/9 and an increase in sgp130 in nasal tissue samples from patients with CRSwNP, although there was no age-related difference in IL-6/sIL-6R production. Additionally, expression of the S100A8/9 gene and protein was increased significantly by IL-6/sIL-6R plus TNF-α in normal human bronchial epithelial cells. This increase was blocked by sgp130. These results suggest that increased sgp130 in older patients may inhibit IL-6 trans-signaling, impair barrier function, and decrease S1008/9 production in elderly patients with CRSwNP. Restoration of barrier function by targeting sgp130 may be a novel treatment strategy.

Role played by interleukin-6 in evoking the exercise pressor reflex in decerebrate rats: effect of femoral artery ligation.

IL-6 signaling via the soluble IL-6 receptor (sIL-6r) has been shown to increase primary afferent responsiveness to noxious stimuli. This finding prompted us to test the hypothesis that IL-6 and sIL-6r would increase the exercise pressor reflex in decerebrate rats with freely perfused femoral arteries. We also tested the hypothesis that soluble glycoprotein (sgp)130, an inhibitor of IL-6/sIL-6r signaling, would decrease the exaggerated exercise pressor reflex that is found in decerebrate rats with ligated femoral arteries. In rats with freely perfused femoral arteries, coinjection of 50 ng of IL-6 and sIL-6r into the arterial supply of the hindlimb significantly increased the peak pressor response to static (control: 14 ± 3 mmHg and IL-6/sIL-6r: 17 ± 2 mmHg, P = 0.03) and intermittent isometric (control: 10 ± 2 mmHg and IL-6/sIL-6r: 15 ± 4 mmHg, P = 0.03) hindlimb muscle contraction. In rats with ligated femoral arteries, injection of 50 ng of sgp130 into the arterial supply of the hindlimb reduced the peak pressor response to static (control: 24 ± 2 mmHg and sgp130: 16 ± 3 mmHg, P = 0.01) and intermittent isometric (control: 16 ± 2 mmHg and sgp130: 13 ± 2 mmHg, P = 0.04) hindlimb muscle contraction, whereas there was no effect of sgp130 on the exercise pressor reflex in rats with freely perfused femoral arteries. We conclude that coinjection of exogenous IL-6 and sIL-6r increased the exercise pressor reflex in rats with freely perfused femoral arteries. More importantly, we also conclude that IL-6 and sIL-6r play an endogenous role in evoking the exercise pressor reflex in rats with ligated femoral arteries but not in rats with freely perfused femoral arteries.

Central inhibition of interleukin-6 trans-signaling during peripheral infection reduced neuroinflammation and sickness in aged mice.

During systemic infection, inflammatory cytokines such as interleukin (IL)-6 are produced in excess in the brain of aged mice and induce severe behavioral deficits. However, no studies have examined how pro-inflammatory IL-6 trans-signaling is involved in the exaggerated production of IL-6 in the aged brain, nor the extent to which IL-6 trans-signaling affects other markers of neuroinflammation, adhesion molecules, and behavior. Therefore, this study investigated in aged mice the presence of IL-6 signaling subunits in microglia; the central effects of soluble gp130 (sgp130)-a natural inhibitor of the IL-6 trans-signaling pathway-on IL-6 production in microglia; and the effects of sgp130 given intracerebroventricularly (ICV) on neuroinflammation and sickness behavior caused by i.p. injection of lipopolysaccharide (LPS). Here we show that microglia isolated from aged mice have higher expression of IL-6 receptor (IL-6R) compared to microglia from adults; and the level of mRNA for ADAM17, the enzyme responsible for shedding membrane-bound IL-6R in trans-signaling, is higher in the hippocampus of aged mice compared to adults. Additionally, we show in aged mice that peripheral LPS challenge elicits a hyperactive IL-6 response in microglia, and selective blockade of trans-signaling by ICV injection of sgp130 mitigates this. The sgp130-associated inhibition of IL-6 was paralleled by amelioration of exaggerated and protracted sickness behavior in aged mice. Taken together, the results show that microglia are important regulators of the IL-6 trans-signaling response in the aged brain and sgp130 exerts an anti-inflammatory effect by inhibiting the pro-inflammatory arm of IL-6 signaling.

Evidence for sustained elevation of IL-6 in the CNS as a key contributor of depressive-like phenotypes.

There is compelling clinical literature implicating a role for cytokines in the pathophysiology of major depressive disorder (MDD). Interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) are pleiotropic inflammatory cytokines that have been reported to be elevated in patients with MDD. The present studies were undertaken to investigate the relationship between IL-6 and IL-1ß in animal models of depressive-like behavior. Analysis of brain tissue homogenates in the cortex of rats subjected to chronic stress paradigms revealed elevated levels of IL-6 protein in the absence of elevations in IL-1ß. Central administration of recombinant mouse IL-6 produced depressive-like phenotypes in mice, which were not accompanied by IL-1ß-induced increases in the brain tissue or IL-1ß-related sickness behavior typical of a general central nervous system inflammatory response. Systemic administration of fluoxetine in the presence of centrally administered IL-6 failed to produce the expected antidepressant-like response in mice relative to sham-infused controls. Further, administration of fluoxetine to mice with endogenous overexpression of brain IL-6 (MRL/MpJ-Fas(LPR/LPR) (LPR mice)) failed to produce the expected antidepressant-like effect relative to fluoxetine-treated control mice (MRL/MpJ(+/+)). Interestingly, blockade of IL-6 trans-signaling by coadministration of a gp130/Fc monomer or an anti-mouse IL-6 antibody with IL-6 prevented the IL-6-induced increases in immobility time as well as attenuated IL-6-induced increases of protein in the cortex. Taken together, these data indicate that elevations in IL-6 may have a pathophysiological role underlying depression and more specifically resistance to current classes of antidepressant medications and suggest that modulation of the IL-6 signaling pathway may have therapeutic potential for treatment-resistant depression.

Interleukin-6 induces S100A9 expression in colonic epithelial cells through STAT3 activation in experimental ulcerative colitis.

BACKGROUND: Intestinal epithelium is essential for maintaining normal intestinal homeostasis; its breakdown leads to chronic inflammatory pathologies, such as inflammatory bowel diseases (IBDs). Although high concentrations of S100A9 protein and interleukin-6 (IL-6) are found in patients with IBD, the expression mechanism of S100A9 in colonic epithelial cells (CECs) remains elusive. We investigated the role of IL-6 in S100A9 expression in CECs using a colitis model. METHODS: IL-6 and S100A9 expression, signal transducer and activator of transcription 3 (STAT3) phosphorylation, and infiltration of immune cells were analyzed in mice with dextran sulfate sodium (DSS)-induced colitis. The effects of soluble gp130-Fc protein (sgp130Fc) and S100A9 small interfering (si) RNA (si-S100A9) on DSS-induced colitis were evaluated. The molecular mechanism of S100A9 expression was investigated in an IL-6-treated Caco-2 cell line using chromatin immunoprecipitation assays. RESULTS: IL-6 concentrations increased significantly in the colon tissues of DSS-treated mice. sgp130Fc or si-S100A9 administration to DSS-treated mice reduced granulocyte infiltration in CECs and induced the down-regulation of S100A9 and colitis disease activity. Treatment with STAT3 inhibitors upon IL-6 stimulation in the Caco-2 cell line demonstrated that IL-6 mediated S100A9 expression through STAT3 activation. Moreover, we found that phospho-STAT3 binds directly to the S100A9 promoter. S100A9 may recruit immune cells into inflamed colon tissues. CONCLUSIONS: Elevated S100A9 expression in CECs mediated by an IL-6/STAT3 signaling cascade may play an important role in the development of colitis.

Cutting edge: Inhibition of IL-6 trans-signaling protects from malaria-induced lethality in mice.

Circulating IL-6 levels correlate with the severity of blood-stage malaria in humans and mouse models, but the impact of IL-6 classic signaling through membrane IL-6Rα, as well as IL-6 trans-signaling through soluble IL-6Rα, on the outcome of malaria has remained unknown. In this study, we created IL-6Rα-deficient mice that exhibit a 50% survival of otherwise lethal blood-stage malaria of the genus Plasmodium chabaudi. Inducing IL-6 trans-signaling by injection of mouse recombinant soluble IL-6Rα in IL-6Rα-deficient mice restores the lethal outcome to malaria infection. In contrast, inhibition of IL-6 trans-signaling via injection of recombinant sGP130Fc protein in control mice results in a 40% survival rate. Our data demonstrate that IL-6 trans-signaling, rather than classic IL-6 signaling, contributes to malaria-induced lethality in mice, preceded by an increased inflammatory response. Therefore, inhibition of IL-6 trans-signaling may serve as a novel promising therapeutic basis to combat malaria.

The STAT3-IGFBP5 axis is critical for IL-6/gp130-induced premature senescence in human fibroblasts.

Cells undergo senescence in response to various conditions, including telomere erosion, oncogene activation and multiple cytokines. One of these cytokines, interleukin-6 (IL­6), not only functions in the immune system, but also promotes cellular senescence and cancer. Here we demonstrate that IL­6 and the soluble IL­6 receptor (sIL­6R) induce premature senescence in normal human fibroblasts by establishing a senescence-inducing circuit involving the signal transducer and activator of transcription 3 (STAT3) and insulin-like growth factor-binding protein 5 (IGFBP5). Stimulating TIG3 fibroblast cells with IL­6/sIL­6R sequentially caused an increase in reactive oxygen species (ROS) as early as day 1, followed by the DNA damage response, p53 accumulation and, finally, senescence on days 8-10. We found that STAT3 was required for the events leading to senescence, including the initial early-phase ROS increase and the induction of IL­1α/ß, IL­6 and CXCL8 mRNAs 4-5 d after IL­6/sIL­6R stimulation, suggesting that STAT3's role is indirect. We searched for STAT3-downstream molecule(s) responsible for the senescence-inducing activity in the supernatants of stimulated TIG3 and identified IGFBP5 as a major STAT3 mediator, because IGFBP5 was expressed from the early phase through the entire senescence process and was responsible for IL­6/STAT3-induced ROS increase and premature senescence. Thus, IL­6/sIL­6R forms a senescence-inducing circuit involving the STAT3-IGFBP5 axis as a key triggering and reinforcing component.

Transsignaling of interleukin-6 crucially contributes to atherosclerosis in mice.

OBJECTIVE: Transsignaling of interleukin (IL)-6 is a central pathway in the pathogenesis of disorders associated with chronic inflammation, such as Crohn disease, rheumatoid arthritis, and inflammatory colon cancer. Notably, IL-6 also represents an independent risk factor for coronary artery disease (CAD) in humans and is crucially involved in vascular inflammatory processes. METHODS AND RESULTS: In the present study, we showed that treatment with a fusion protein of the natural IL-6 transsignaling inhibitor soluble glycoprotein 130 (sgp130) and IgG1-Fc (sgp130Fc) dramatically reduced atherosclerosis in hypercholesterolemic Ldlr(-/-) mice without affecting weight gain and serum lipid levels. Moreover, sgp130Fc treatment even led to a significant regression of advanced atherosclerosis. Mechanistically, endothelial activation and intimal smooth muscle cell infiltration were decreased in sgp130Fc-treated mice, resulting in a marked reduction of monocyte recruitment and subsequent atherosclerotic plaque progression. Of note, patients with CAD exhibited significantly lower plasma levels of endogenous sgp130, suggesting that a compromised counterbalancing of IL-6 transsignaling may contribute to atherogenesis in humans. CONCLUSIONS: These data clarify, for the first time, the critical involvement of, in particular, the transsignaling of IL-6 in CAD and warrant further investigation of sgp130Fc as a novel therapeutic for the treatment of CAD and related diseases.

Interleukin-6 trans-signaling in the senescent mouse brain is involved in infection-related deficits in contextual fear conditioning.

Excessive production of pro-inflammatory cytokines in the senescent brain in response to peripheral immune stimulation is thought to induce behavioral pathology, however, few studies have examined if the increase in pro-inflammatory cytokines is accompanied by an increase in cytokine signaling. Here, we focused on IL-6 as a prototypic pro-inflammatory cytokine and used phosphorylated STAT3 as a marker of IL-6 signaling. In an initial study, IL-6 mRNA and the magnitude and duration of STAT3 activation were increased in the hippocampus of senescent mice compared to adults after i.p. injection of LPS. The LPS-induced increase in STAT3 activity was ablated in aged IL-6(-/-) mice, suggesting IL-6 is a key driver of STAT3 activity in the aged brain. To determine if IL-6 activated the classical or trans-signaling pathway, before receiving LPS i.p., aged mice were injected ICV with sgp130, an antagonist of the trans-signaling pathway. Importantly, the LPS-induced increases in both IL-6 and STAT3 activity in the hippocampus were inhibited by sgp130. To assess hippocampal function, aged mice were injected ICV with sgp130 and i.p. with LPS immediately after the acquisition phase of contextual fear conditioning, and immobility was assessed in the retention phase 48h later. LPS reduced immobility in aged mice, indicating immune activation interfered with memory consolidation. However, sgp130 blocked the deficits in contextual fear conditioning caused by LPS. Taken together, the results suggest IL-6 trans-signaling is increased in the senescent brain following peripheral LPS challenge and that sgp130 may protect against infection-related neuroinflammation and cognitive dysfunction in the aged.

Inhibition of interleukin-6 trans-signaling in the brain facilitates recovery from lipopolysaccharide-induced sickness behavior.

BACKGROUND: Interleukin (IL)-6 is produced in the brain during peripheral infection and plays an important but poorly understood role in sickness behavior. Therefore, this study investigated the capacity of soluble gp130 (sgp130), a natural inhibitor of the IL-6 trans-signaling pathway to regulate IL-6 production in microglia and neurons in vitro and its effects on lipopolysaccharide (LPS)-induced sickness behavior in vivo. METHODS: A murine microglia (BV.2) and neuronal cell line (Neuro.2A) were used to study the effects of stimulating and inhibiting the IL-6 signaling pathway in vitro. In vivo, adult (3-6 mo) BALB/c mice received an intracerebroventricular (ICV) injection of sgp130 followed by an intraperitoneal (i.p.) injection of LPS, and sickness behavior and markers of neuroinflammation were measured. RESULTS: Soluble gp130 attenuated IL-6- and LPS-stimulated IL-6 receptor (IL-6R) activation along with IL-6 protein release in both microglial (BV.2) and neuronal (Neuro.2A) cell types in vitro. Moreover, in vivo experiments showed that sgp130 facilitated recovery from LPS-induced sickness, and this sgp130-associated recovery was paralleled by reduced IL-6 receptor signaling, mRNA, and protein levels of IL-6 in the hippocampus. CONCLUSIONS: Taken together, the results show that sgp130 may exert an anti-inflammatory effect on microglia and neurons by inhibiting IL-6 binding. These data indicate that sgp130 inhibits the LPS-induced IL-6 trans-signal and show IL-6 and its receptor are involved in maintaining sickness behavior.

Interleukin-6: a local pain trigger?

Pain management in conditions of chronic inflammation is a clinical challenge, and increasing our understanding of the mechanisms driving this type of pain is important. In the previous issue of Arthritis Research & Therapy, Boettger and colleagues examine the role of IL-6 in antigen-induced arthritis using the IL-6 neutralizing soluble glycoprotein 130 and link IL-6 to a pathophysiological role in the generation of pain, independent of the proinflammatory properties of IL-6. The findings presented in this study add to a growing body of evidence highlighting the role of IL-6 in the induction and maintenance of pain.

Correlation of soluble gp130 serum concentrations with arterial blood pressure.

OBJECTIVES: An increased blood pressure can elicit remodeling of the cardiovascular system. Experimental data have implicated gp130, a subunit of the receptor for interleukin-6 (IL-6)-related cytokines, in the regulation of proliferation and apoptosis of cardiomyocytes and vascular smooth muscle cells (VSMC). Here, we investigate whether serum soluble gp130 concentrations correlate with blood pressure in humans, whether gp130 expression in the aorta differs between hypertensive and control rats, and whether angiotensin II or endothelin regulate gp130 expression in human VSMC. METHODS: We measured serum concentrations of soluble gp130, IL-6, the soluble IL-6 receptor, and the intima-media thickness of the common carotid artery in stroke patients (n = 48) and in elderly controls (n = 48). Furthermore, soluble gp130 levels were measured in young controls (n = 200). Expression of gp130 in Wistar-Kyoto (n = 12), spontaneously hypertensive rats (n = 12), and human VSMC was detected by real-time reverse transcription-PCR and immunohistochemistry. RESULTS: Soluble gp130 serum concentrations correlated with blood pressure in stroke patients and in elderly and young controls and with the intima-media thickness of the common carotid artery in stroke patients. The hypothesis that elevated soluble gp130 derives from the vascular system was supported by the enhanced expression of gp130 in the aortic wall of spontaneously hypertensive rats. Furthermore, treatment of human VSMC with angiotensin II stimulated gp130 expression. CONCLUSION: Our data suggest that soluble gp130 serum concentrations are correlated with blood pressure and may reflect vascular remodeling in response to arterial hypertension.

Structure-guided optimization of the interleukin-6 trans-signaling antagonist sgp130.

Binding of interleukin-6 (IL-6) to its specific receptor IL-6R is a prerequisite for the activation of the signal-transducing receptor glycoprotein 130 (gp130). A soluble form of the IL-6R (sIL-6R) in complex with IL-6 can activate cells lacking membrane-bound IL-6R (trans-signaling). IL-6-trans-signaling is counterbalanced by a naturally occurring, soluble form of gp130 (sgp130), whereby signaling via the membrane-bound IL-6R is not affected. Many inflammatory and neoplastic disorders are driven by IL-6 trans-signaling. By analysis of the three-dimensional structure of gp130 in complex with IL-6 and sIL-6R, we identified amino acid side chains in gp130 as candidates for the generation of sgp130 muteins with increased binding affinity to IL-6/sIL-6R. In addition, with information from modeling and NMR analysis of the membrane proximal domain of gp130, we generated a more stable variant of sgp130Fc. Proteins were tested for binding to the IL-6/sIL-6R-complex, for inhibition of IL-6/sIL-6R-induced cell proliferation and of acute phase gene expression. Several mutations showed an additive effect in improving the binding affinity of human sgp130 toward human IL-6/sIL-6R. Finally, we demonstrate the species specificity of these mutations in the optimal triple mutein (T102Y/Q113F/N114L) both in vitro and in a mouse model of acute inflammation.

Notch ligand Delta-1 differentially modulates the effects of gp130 activation on interleukin-6 receptor alpha-positive and -negative human hematopoietic progenitors.

Interleukin (IL)-6 plays pleiotropic roles in human hematopoiesis and immune responses by acting on not only the IL-6 receptor-alpha subunit (IL-6Ralpha)(+) but also IL-6Ralpha(-) hematopoietic progenitors via soluble IL-6R. The Notch ligand Delta-1 has been identified as an important modulator of the differentiation and proliferation of human hematopoietic progenitors. Here, it was investigated whether these actions of IL-6 are influenced by Delta-1. When CD34(+)CD38(-) hematopoietic progenitors were cultured with stem cell factor, flt3 ligand, thrombopoietin and IL-3, Delta-1, in combination with the IL-6R/IL-6 fusion protein FP6, increased the generation of glycophorin A(+) erythroid cells but counteracted the effects of IL-6 and FP6 on the generation of CD14(+) monocytic and CD15(+) granulocytic cells. Although freshly isolated CD34(+)CD38(-) cells expressed no or only low levels of IL-6Ralpha, its expression was increased in myeloid progenitors after culture but remained negative in erythroid progenitors. It was found that Delta-1 acted in synergy with FP6 to enhance the generation of erythroid cells from the IL-6Ralpha(-) erythroid progenitors. In contrast, Delta-1 antagonized the effects of IL-6 and FP6 on the development of monocytic and granulocytic cells, as well as CD14(-)CD1a(+) dendritic cells, from the IL-6Ralpha(+) myeloid progenitors. These results indicate that Delta-1 interacts differentially with gp130 activation in IL-6Ralpha(-) erythroid and IL-6Ralpha(+) myeloid progenitors. The present data suggest a divergent interaction between Delta-1 and gp130 activation in human hematopoiesis.

Inhibition of IL-6-dependent growth of myeloma cells by an acidic peptide repressing the gp130-mediated activation of Src family kinases.

An acidic domain (AD) of gp130 was previously found to interact with the Src family kinase (SFK) Hck. Here, the influence of myristoylated peptides derived from this AD was assessed in the mouse myeloma cell line, 7TD1. The IL-6-dependent growth of 7TD1 cells was reduced by approximately 75%, if 100 microM of myristoylated 18mer peptide (18AD) was included in the growth medium, but was unaffected by a control peptide with scrambled sequence (18sc). A similar differential inhibition by peptides 18AD and 18sc was observed for the erythropoietin-dependent growth of BaF-EH cells expressing chimeric erythropoietin receptor-gp130 and human Hck and for the human myeloma cell line INA-6. While the peptide 18AD concentration inhibiting 50% was approximately 30 microM in 7TD1 and BaF-EH cells, peptide 18AD did not significantly inhibit growth of IL-6-independent MM1.S myeloma and OKT1 hybridoma cells or of BaF-EH cells supplied with IL-3. Treatment with 100 microM peptide 18AD caused the same degree or 60% of apoptosis induction as IL-6 deprivation in 7TD1 or INA-6 cells, respectively. Co-immunoprecipitation experiments revealed that peptide 18AD interfered with the association of Hck and gp130 in 7TD1 lysates in a concentration-dependent manner. IL-6-treatment of INA-6 cells induced the kinase activities of Fyn, Lyn and Hck, but not Src, and the IL-6-induced SFK activities were inhibited by peptide 18AD. Expression in 7TD1 cells of a kinase-inactive Hck mutant (K269R) elicited a dominant-negative effect on cell number increases providing further evidence that SFKs are required for gp130 signalling in myeloma cells.

Sensitization of unmyelinated sensory fibers of the joint nerve to mechanical stimuli by interleukin-6 in the rat: an inflammatory mechanism of joint pain.

OBJECTIVE: Pain during mechanical stimulation of the joint and spontaneous pain are major symptoms of arthritis. An important neuronal process of mechanical hypersensitivity of the joint is the sensitization of thin myelinated Adelta fibers and unmyelinated C fibers innervating the joint. Because interleukin-6 (IL-6) is a major inflammatory mediator, we investigated whether this cytokine has the potential to sensitize joint afferents to mechanical stimuli. METHODS: In electrophysiologic experiments conducted on anesthetized rats, action potentials were recorded from afferent fibers supplying the knee joint. Responses to innocuous and noxious rotation of the tibia against the femur in the knee joint were monitored before and 1-2 hours after injection of test compounds into the joint cavity. RESULTS: Injection of IL-6 and coinjection of IL-6 plus soluble IL-6 receptor (sIL-6R) caused a gradual increase in the responses of C fibers to innocuous and noxious rotation within 1 hour. The increase in responses to IL-6 and IL-6 plus sIL-6R was prevented by coadministration of soluble glycoprotein 130 (sgp130), but sgp130 did not reverse established mechanical hyperexcitability. Responses of Adelta fibers were not altered by the compounds. While injection of sIL-6R alone into the normal knee joint did not influence responses to mechanical stimulation, injection of sIL-6R into the acutely inflamed knee joint caused an increase in responses. CONCLUSION: IL-6 has the potential to sensitize C fibers in the joint to mechanical stimulation. Thus, IL-6 contributes to mechanical hypersensitivity, most likely due to an action of IL-6 on nerve fibers themselves.

Interleukin-6 trans-signaling in inflammatory bowel disease.

The pathogenesis of inflammatory bowel disease (IBD) is complex, involving a wide range of molecules including cytokines. Recent investigations support the important role of an interleukin-6 (IL-6) signaling pathway in the development of IBD. However, the molecular mechanisms of this pathway in the intestine remain incompletely understood. The circulating and intestinal levels of IL-6 as well as soluble IL-6 receptor (sIL-6R) are increased in patients with IBD. It is remarkable that the mucosal T cells of IBD patients are extremely resistant to apoptosis and that a large fraction of these cells express membrane-bound gp130 but not IL-6R. The accumulated evidence strongly supports the hypothesis that the development and perpetuation of IBD relies on the increased formation of IL-6/sIL-6R complexes interacting with membrane-bound gp130 on T cells via trans-signaling. These studies suggest that IL-6 trans-signaling may play a role in the development of IBD; they therefore imply the possibility of a selective therapeutic strategy to target this signaling.