Soluble gp130 is the natural inhibitor of soluble interleukin-6 receptor transsignaling responses.

Signal transduction in response to interleukin-6 (IL-6) requires binding of the cytokine to its receptor (IL-6R) and subsequent homodimerization of the signal transducer gp130. The complex of IL-6 and soluble IL-6R (sIL-6R) triggers dimerization of gp130 and induces responses on cells that do not express membrane bound IL-6R. Naturally occurring soluble gp130 (sgp130) can be found in a ternary complex with IL-6 and sIL-6R. We created recombinant sgp130 proteins that showed binding to IL-6 in complex with sIL-6R and inhibited IL-6/sIL-6R induced proliferation of BAF/3 cells expressing gp130. Surprisingly, sgp130 proteins did not affect IL-6 stimulated proliferation of BAF/3 cells expressing gp130 and membrane bound IL-6R, indicating that sgp130 did not interfere with IL-6 bound to IL-6R on the cell surface. Additionally, sgp130 partially inhibited proliferation induced by leukemia inhibitory factor (LIF) and oncostatin M (OSM) albeit at higher concentrations. Recombinant sgp130 protein could be used to block the anti-apoptotic effect of sIL-6R on lamina propria cells from Crohn disease patients. We conclude that sgp130 is the natural inhibitor of IL-6 responses dependent on sIL-6R. Furthermore, recombinant sgp130 is expected to be a valuable therapeutic tool to specifically block disease states in which sIL-6R transsignaling responses exist, e.g. in morbus Crohn disease.     

IL-6 trans-signaling system in intra-amniotic inflammation, preterm birth, and preterm premature rupture of the membranes

Classic IL-6 signaling is conditioned by the transmembrane receptor (IL-6R) and homodimerization of gp130. During trans-signaling, IL-6 binds to soluble IL-6R (sIL-6R), enabling activation of cells expressing solely gp130. Soluble gp130 (sgp130) selectively inhibits IL-6 trans-signaling. To characterize amniotic fluid (AF) IL-6 trans-signaling molecules (IL-6, sIL-6R, sgp130) in normal gestations and pregnancies complicated by intra-amniotic inflammation (IAI), we studied 301 women during second trimester (n = 39), third trimester (n = 40), and preterm labor with intact (n = 131, 85 negative IAI and 46 positive IAI) or preterm premature rupture of membranes (PPROM; n = 91, 61 negative IAI and 30 positive IAI). ELISA, Western blotting, and real-time RT-PCR were used to investigate AF, placenta, and amniochorion for protein and mRNA expression of sIL-6R, sgp130, IL-6R, and gp130. Tissues were immunostained for IL-6R, gp130, CD15(+) (polymorphonuclear), and CD3(+) (T cell) inflammatory cells. The ability of sIL-6R and sgp130 to modulate basal and LPS-stimulated release of amniochorion matrix metalloprotease-9 was tested ex vivo. We showed that in physiologic gestations, AF sgp130 decreases toward term. AF IL-6 and sIL-6R were increased in IAI, whereas sgp130 was decreased in PPROM. Our results suggested that fetal membranes are the probable source of AF sIL-6R and sgp130. Immunohistochemistry and RT-PCR revealed increased IL-6R and decreased gp130 expression in amniochorion of women with IAI. Ex vivo, sIL-6R and LPS augmented amniochorion matrix metalloprotease-9 release, whereas sgp130 opposed this effect. We conclude that IL-6 trans-signaling molecules are physiologic constituents of the AF regulated by gestational age and inflammation. PPROM likely involves functional loss of sgp130.     

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.     

Inhibition of classic signaling is a novel function of soluble glycoprotein 130 (sgp130), which is controlled by the ratio of interleukin 6 and soluble interleukin 6 receptor

IL-6 trans-signaling via the soluble IL-6 receptor (sIL-6R) plays a critical role in chronic inflammation and cancer. Soluble gp130 (sgp130) specifically inhibits IL-6 trans-signaling but was described to not interfere with classic signaling via the membrane-bound IL-6R. Physiological and most pathophysiological conditions are characterized by a molar excess of serum sIL-6R over IL-6 characterized by free IL-6 and IL-6 found in IL-6·sIL-6R complexes allowing both classic and trans-signaling. Surprisingly, under these conditions, sgp130 was able to trap all free IL-6 molecules in IL-6·sIL-6R·sgp130 complexes, resulting in inhibition of classic signaling. Because a significant fraction of IL-6 molecules did not form complexes with sIL-6R, our results demonstrate that compared with the anti-IL-6R antibody tocilizumab or the anti-trans-signaling monoclonal antibody 25F10, much lower concentrations of the dimeric sgp130Fc were sufficient to block trans-signaling. In vivo, sgp130Fc blocked IL-6 signaling in the colon but not in liver and lung, indicating that the colon is a prominent target of IL-6 trans-signaling. Our results point to a so far unanticipated role of sgp130 in the blockade of classic signaling and indicate that in vivo only low therapeutic concentrations of sgp130Fc guarantee blockade of IL-6 trans-signaling without affecting IL-6 classic signaling.     

Interleukin-6 receptor signaling. II. Bio-availability of interleukin-6 in serum.

Interleukin-6 (IL-6) is used as a growth factor by various tumor cells. It binds to a gp80 specific receptor (IL-6R) and then to a gp130 transducing chain. Both receptor chains are released as soluble functional proteins which circulate in biological fluids. With a view to studying the physiological role of these soluble receptors, both proteins were purified from human plasma. Surface plasmon resonance was used to measure the kinetic constants of equilibria between IL-6 and natural sIL-6R, and between the IL-6/sIL-6R complex and soluble gp130. Kd values were found to be 0. 9 and 2.3 nM respectively. Soluble natural IL-6R and gp130 were also found to interact with a Kd of 2.8 nM in the absence of IL-6. By using these Kd values, a mathematical simulation predicted that 1) within a large range of IL-6, sIL-6R and sgp130 concentrations, free IL-6 represents 30% of the total circulating cytokine, 2) sIL-6R overconcentrations lead to dramatic changes of the concentration of free IL-6, 3) increased concentrations of sgp130 should produce an efficient buffering effect on the IL-6/sIL-6R complex without incidence on the level of free IL-6. According to this model, the IL-6/sIL-6R complex appears to be an important support of IL-6 signaling in the most commonly encountered in vivo situations. The concentration of this complex is directly under the control of the concentration of sIL-6R; its bio-availability should be efficiently buffered by increased sgp130 concentrations.     

Secretion of IL-6, IL-11 and LIF by human cardiomyocytes in primary culture

Interleukin (IL)-6-type cytokines are multifunctional proteins involved in cardiac hypertrophy and myocardial protection. Recent studies, performed on animal models, report the production of these cytokines by heart. The aim of this study was to analyse the capacity of myocytes and fibroblasts isolated from human atrium to secrete IL-6, leukaemia inhibitory factor (LIF), cardiotrophin-1 (CT-1), IL-11, oncostatin M (OSM), ciliary neurotrophic factor (CNTF) and the soluble receptor subunits sIL-6R and sgp130 during primary culture. We detected LIF, IL-11, sgp130 and a large amount of IL-6, but not OSM, CT-1, CNTF nor IL-6R in these culture supernatants. Both cardiomyocytes and fibroblasts are able to spontaneously produce IL-6. The increase of IL-6 production all along the culture period appears to be the consequence of fibroblast proliferation and gp130 stimulation. This is the first demonstration that human cardiac cells are able to secrete IL-6, but also LIF and IL-11 in vitro. These cytokines could be involved in an autocrine and/or a paracrine networks regulating myocardial cyto-protection, hypertrophy and fibrosis.     

Role of interleukin-15 and interleukin-18 in the secretion of sIL-6R and sgp130 by human neutrophils

BACKGROUND: Available data indicate that neutrophils (PMN) produce a wide range of cytokines with the potential to modulate immune response. Recent investigation have shown that interleukin (IL)-15 and IL-18 potentiated several functions of normal neutrophils. It has been reported that IL-18-induced cytokine production may be significantly enhanced by coincident addition of IL-15. AIMS: In the present study we compared the effect of recombinant human (rh)IL-15 and rhIL-18 as well as effect of a rhIL-15 and rhIL-18 combination on the induction secretion of sIL-6Ralpha and sgp130 by human neutrophils. METHODS: PMN were isolated from heparinized whole blood of healthy persons. The PMN were cultured for 18 h at 37 degrees C in a humidified incubator with 5% CO(2). rhIL-15 and/or rhIL-18 and lipopolysaccharide were tested to PMN stimulation. The culture supernatants of PMN were removed and examined for the presence of sIL-6R and sgp130 by human enzyme-linked immunosorbent assay kits. Cytoplasmic protein fractions of PMN were analysed for the presence of sIL-6R and sgp130 by western blotting using monoclonal antibodies capable of detecting these proteins. Cells were lysed and cytoplasmic proteins were electrophoresed on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The resolved proteins were transferred onto nitrocellulose and incubated with the primary monoclonal antibodies anti-sIL-6R and anti-sgp130. The membranes were incubated at room temperature with alkaline phosphatase anti-mouse immunoglobulin G. Immunoreactive protein bans were visualized by an AP Conjugate Substrate Kit. RESULTS AND CONCLUSIONS: The results of our investigation revealed that IL-15 alone, similarly to IL-18, has no significant ability for the regulation of both soluble IL-6 receptors, sIL-6R and sgp130, released by human neutrophils. It is interesting to note that the secretion of sgp130 was changed after PMN stimulation with rhIL-15 in the presence of rhIL-18. The combination of rhIL-15 and rhIL-18 was shown to induce PMN to secretion relatively higher amounts of sgp130 compared with the stimulation of PMN with rhIL-15 alone and rhIL-18 alone. The results obtained suggest that IL-15 and IL-18, belonging to the inflammatory cytokines, through the regulation of sgp130 secretion must be also considered as anti-inflammatory mediators that may influence the balance reactions mediated by the IL-6 cytokine family.     

The role of transsignalling via the agonistic soluble IL-6 receptor in human diseases

The activation of cells that do not express the membrane bound interleukin-6 6 receptor (IL-6R) by IL-6 and the soluble IL-6 receptor (sIL-6R) is termed transsignalling. Transsignalling may be an pathogenetic factor in human diseases as diverse as multiple myeloma (MM), Castleman's disease, prostate carcinoma, Crohn's disease, systemic sclerosis, Still's disease, osteoporosis and cardiovascular diseases. IL-6 and sIL-6R may directly or indirectly enhance their own production on endothelial or bone marrow stromal cells. Positive feedback autocrine loops thus created in affected organs may either cause or maintain disease progression. In autoimmune or vasculitic disease, the ability of the IL-6/sIL-6R complex to inhibit apoptosis of autoreactive T-cells may be central to the development of tissue specific autoimmunity. The anti-apoptotic effect of the IL-6/sIL-6R complex may be involved in tumour genesis and resistance to chemotherapy.Only in rare cases, where counterregulation has failed, there is a notable systemic effect of IL-6/sIL-6R. Appropriate animal models are necessary to establish the pathogenetic role of the IL-6/sIL-6R complex. A specific treatment option for diseases influenced by the sIL-6R could be based on gp130-Fc, a soluble gp130 (sgp130) linked to the Fc-fragment of IgG1. gp130-Fc has shown efficacy in vivo in animal models of Crohn's disease.     

Interleukin-6 receptor signaling. I. gp80 and gp130 receptor interaction in the absence of interleukin-6

Interleukin-6 (IL-6) is used as a growth factor by various tumor cells. It binds to a gp80 specific receptor (IL-6R) and then to a gp130 transducing chain. Both receptor chains are released as soluble functional proteins which circulate in biological fluids. To study the physiological role of these soluble receptors, both proteins were purified from human plasma and the kinetic constants of equilibria between IL-6 and its natural soluble IL-6R (sIL-6R) and gp130 receptor (sgp130) were measured using surface plasmon resonance analysis. Unexpectedly, natural sIL-6R and natural sgp130 were found to interact (Kd = 2.8 nM) in the absence of IL-6. No interaction was seen between the recombinant soluble receptors or between either natural soluble receptor and its recombinant partner. This binary complex was not due to copurification of IL-6 and was detected in human plasma of healthy donors. It results from either direct interaction between the two natural soluble receptors or indirect binding mediated by a yet unidentified copurified plasma molecule playing the role of an IL-6 antagonist. Once formed, the binary complex was found to be unable to bind IL-6. Soluble gp130 had already been shown to inhibit IL-6 signaling by inactivating the IL-6/IL-6R complex. In addition we show that, in the absence of IL-6, circulating natural sgp130 is able to inhibit directly the circulating sIL-6R that is a strong synergic molecule of IL-6 signaling.     

Response of plasma IL-6 and its soluble receptors during submaximal exercise to fatigue in sedentary middle-aged men

The pleiotropic cytokine interleukin-6 (IL-6) has been demonstrated to increase during exercise. Little is known regarding the response of the soluble IL-6 receptors (sIL-6R and sgp130) during such exercise. The aim of the current study was to investigate the response of plasma IL-6, sIL-6R and sgp130 during fatiguing submaximal exercise in humans. Twelve participants underwent an incremental exercise test to exhaustion and one week later performed a submaximal exercise bout (96 ± 6% lactate threshold) to volitional exhaustion. Blood samples taken at rest and immediately post exercise were analyzed for IL-6, sIL-6R and sgp130. IL-6 increased (P < 0.01) by 8.4 ± 8.9 pg ml⁻¹ (75.7%) during the exercise period. sIL-6R and sgp130 also increased (P < 0.05) by 2.7 ± 3.9 ng ml⁻¹ (9.6%) and 37.7 ± 55.6 ng ml⁻¹ (9.6%), respectively. The current study is the first investigation to demonstrate that alongside IL-6, acute exercise stress results in an increase in both sIL-6R and sgp130.     

Soluble glycoprotein 130 is inversely related to severity of coronary atherosclerosis

Purpose: Recent studies indicate that the effects of interleukin 6 (IL-6) realized via soluble IL-6 receptor (sIL-6R) facilitate the development of various pathological processes. Soluble gp130 (sgp130) is a naturally occurring inhibitor of signal transduction via this pathway. In this study, we assessed the relationship between circulating levels of IL-6, sIL-6R and sgp130 and severity of coronary atherosclerosis in patients with stable coronary artery disease (CAD).

Methods: Plasma levels of IL-6, sIL-6R and sgp130 were measured in patients with atherosclerotic coronary lesions (n?=?128, group 1) and with intact coronary arteries (n?=?48, group 2). The severity of coronary atherosclerosis was evaluated by the number of affected arteries and by Gensini Score index.

Results: Circulating IL-6 levels in group 1 were significantly higher than those in group 2. The levels of sIL-6R did not differ considerably in both the groups. The levels of sgp130 in group 1 were significantly lower than in group 2. A negative correlation has been revealed between sgp130 levels and the number of affected coronary arteries and Gensini Score index.

Conclusions: Serum concentration of sgp130 in patients with stable CAD is inversely related to severity of coronary damage. Low sgp130 level may serve as an additional indicator of coronary atherosclerosis severity.     

The soluble Interleukin 6 receptor: generation and role in inflammation and cancer

Soluble cytokine receptors are frequently found in human serum, most of them possessing antagonistic properties. The Interleukin 6 receptor (IL-6R) is found as a transmembrane protein on hepatocytes and subsets of leukocytes, but soluble isoforms of the IL-6R (sIL-6R) are generated by alternative splicing or by limited proteolysis of the A Disintegrin And Metalloproteinases (ADAM) gene family members ADAM10 and ADAM17. Importantly, the sIL-6R in complex with its ligand Interleukin 6 (IL-6) has agonistic functions and requires cells expressing the signal transducing ß-receptor gp130 but not the membrane-bound IL-6R. We have called this process IL-6 trans-signaling. Naturally occurring isoforms of soluble gp130 (sgp130), which are generated by alternative splicing, are natural inhibitors of IL-6 trans-signaling, leaving IL-6 classic signaling via the membrane-bound IL-6R unaffected. We used recombinant sgp130Fc protein and recently generated transgenic mice expressing high levels of sgp130Fc to discriminate between classic and trans-signaling in vivo, and demonstrated that IL-6 trans-signaling is critically involved in generation and maintenance of several inflammatory and autoimmune diseases including chronic inflammatory bowel disease, rheumatoid arthritis, peritonitis and asthma, as well as inflammation-induced colon cancer.     

Serum levels of IL-6 type cytokines and soluble IL-6 receptors in active B-cell chronic lymphocytic leukemia and in cladribine induced remission

We have investigated the serum concentrations of interleukin-6 (IL-6) and two IL-6 family cytokines-oncostatin M (OSM) and leukemia inhibitory factor (LIF)-in 63 patients with B-cell chronic lymphocytic leukemia (B-CLL) and 17 healthy controls using the enzyme-linked immunosorbent assay (ELISA) method. Simultaneously, we measured the serum levels of the soluble forms of two subunits of the IL-6 receptor complex-ligand binding glycoprotein 80 (sIL-6R) and glycoprotein 130 (sgp130). The cytokines and receptors were evaluated in 25 untreated patients and 38 patients treated with cladribine (2-CdA), as well as in 17 healthy controls. We have correlated the serum levels of these proteins with Rai's clinical stage of the disease, the response to 2-CdA treatment and some hematological parameters. We have also evaluated the correlation of the IL-6 serum level with the concentration of OSM and IL-6 soluble receptors. IL-6 was measurable in 62/63 (98.4%), OSM in 20/25 (80%) of untreated and 14/38 (37.8%) of the treated patients. sIL-6R and sgp130 were detectable in all 63 patients and LIF in none of the CLL patients. IL-6 serum level in untreated patients was not significantly different as compared to its concentration in the control group (P>0.05). However, in the patients treated with 2-CdA the IL-6 level was significantly lower (P<0.02), and the lowest concentration was found in the patients with complete remission (CR; median 1.4pg/ml; P<0.02). The concentration of sIL-6R was significantly higher in untreated (median 61.8 ng/ml) and treated (median 50.1 ng/ml) CLL patients when compared to normal persons (median 41.2 ng/ml; P=0.04; P<0.001, respectively). There was no difference between the sIL-6R levels in the patients with CR and the healthy controls. In non-responders sIL-6R concentration was the highest and similar to its level in the untreated patients. OSM level was higher in the untreated patients (median 1.8pg/ml) than in the normal controls (median 0.0pg/ml; P<0.001) and in the CR patients (median 0.0pg/ml; P<0.03). The serum concentration of sgp130 was similar in the untreated (median 480 pg/ml) and treated (median 470 pg/ml) patients, as well as in the healthy persons (median 420 pg/ml; P>0.05). We have found significant positive correlation between the levels of sIL-6R and the lymphocytes count in CLL patients (p=0.423; P<0.001). In addition, sIL-6R and OSM serum concentrations correlated also with CLL Rai stage. In conclusion, the serum level of IL-6, OSM and sIL-6R, but not LIF and sgp130, are useful indicators of CLL activity.     

The structure of the unliganded extracellular domain of the interleukin-6 signal transducer gp130 in solution

Interleukin-6 (IL-6) plays an important role in immune responses and signals via two different pathways. When IL-6 binds to its non-signalling membrane-bound receptor (IL-6R), a non-covalent dimer of the ubiquitous interleukin-6 signal transducer gp130 is recruited to initiate intracellular signalling cascades. This so-called classical signalling pathway is restricted to cells expressing the membrane-bound IL-6R, such as hepatocytes and certain leukocytes. In addition, an alternative trans-signalling pathway uses soluble forms of IL-6R (sIL-6R) in complex with IL-6 to activate cells expressing gp130, but not membrane-bound IL-6R. In both cases, a tetrameric or hexameric signalling complex consisting of two gp130 molecules and one or two molecules each of IL-6 and (s)IL-6R is formed. The structure of the hexameric complex of the ligand-binding domains of gp130 (D1-D3) with IL-6 and sIL-6R has been solved by X-ray crystallography as well as the full-length extracellular part of gp130 (D1-D6) as a monomer. Since gp130 exists as a preformed dimer on the cell surface, we used a sgp130Fc fusion protein - consisting of two extracellular gp130 regions (D1-D6) dimerised by an IgG1-Fc part - to study the structure of unliganded gp130 extracellular domains in solution by small-angle X-ray scattering (SAXS). The SAXS data indicated that sgp130Fc forms a rigid molecule in solution. The low resolution structural model reveals an elongated assembly with an Fc base and two gp130 arms, whereby the orientation of the ligand-binding domains D1-D3 with respect to the membrane-proximal domains D4-D6 differs from that in the crystallographic monomer. Functional implications of these findings are discussed.     

Shedding of the interleukin-6 (IL-6) receptor (gp80) determines the ability of IL-6 to induce gp130 phosphorylation in human osteoblasts

Human osteoblasts produce interleukin-6 (IL-6) and respond to IL-6 in the presence of soluble IL-6 receptor (sIL-6R), but the cell surface expression of IL-6R and the mechanism of sIL-6R production are largely unknown. Three different human osteoblast-like cell lines (MG-63, HOS, and SaOS-2) and bone marrow-derived primary human osteoblasts expressed both IL-6R and gp130 as determined by flow cytometry and immunoprecipitation. However, the membrane-bound IL-6R was nonfunctional, as significant tyrosine phosphorylation of gp130 did not occur in the presence of IL-6. Phorbol myristate acetate induced a dramatic increase of both IL-6R shedding (i.e. the production of sIL-6R) and IL-6 release in osteoblast cultures, but the cell surface expression of gp130 remained unchanged. IL-6 complexed with sIL-6R, either exogenously introduced or derived from the nonfunctional cell surface form by shedding, induced rapid tyrosine phosphorylation of gp130. This effect was inhibited by neutralizing antibodies to either sIL-6R or gp130, indicating that the gp130 activation was induced by IL-6/sIL-6R/gp130 interaction. Protein kinase C inhibitors blocked phorbol myristate acetate-induced and spontaneous shedding of IL-6R resulting in the absence of sIL-6R in the culture medium, which in turn also prevented the activation of gp130. In conclusion, human osteoblasts express cell surface IL-6R, which is unable to transmit IL-6-induced signals until it is shed into its soluble form. This unique mechanism provides the flexibility for osteoblasts to control their own responsiveness to IL-6 via the activation of an IL-6R sheddase, resulting in an immediate production of functionally active osteoblast-derived sIL-6R.     

The soluble IL-6 receptors: serum levels and biological function.

IL-6 exerts its biological activities through interaction with specific receptors expressed on the surface of target cells. IL-6 binds first to a low-affinity (10(-9) M) subunit, a 80 kDa glycoprotein also called gp80 or IL-6R alpha. The IL-6/IL-6R alpha complex recruits the signal-transducing b subunit, a 130 kDa glycoprotein called gp130. The association of gp130 with IL-6 and IL-6R alpha leads to the formation of the high-affinity IL-6 receptor complex, to the linkage of two gp130 subunits and to signal transduction. Soluble forms of both receptors have been described and found in biological fluids. Soluble cytokine receptors are generated by either proteolytic cleavage of their membrane moiety or by alternative splicing. Both mechanisms have been described for sIL-6R and sgp130 formation. Interestingly, the association of IL-6 with the soluble form of IL-6R alpha is capable of eliciting a biological response in cells that express only the membrane gp130. This type of activation, called "trans-signalling", renders virtually all cells capable of responding to IL-6/sIL-6R alpha complexes, making for a large new spectrum of IL-6 activities, ranging from the control of the immune response to involvement in pathological states. In this review the biological activities of IL-6 will be considered in the light of new knowledge concerning the association of IL-6 and the soluble IL-6 receptors.     

The role of IL-6/sIL-6R complex and its natural inhibitor sgp130 in modulation of inflammatory process

IL-6/sIL-6R complex belongs to one of the most pleiotropic ligand-receptor system. Participating in leukocytes migration and apoptosis it plays a crucial role in modulation of inflammatory process. Firstly it contributes to resolution of acute inflammatory response regulating a maintaining of organism's homeostasis. Secondly it is a main factor responsible for transition between acute and chronic inflammatory reaction, that underlies the pathogenesis of chronic inflammatory diseases. Presented work focus on the IL-6/sIL-6R structure, function, formation, mechanism of action as well as the role of its natural inhibitor sgp130 in mentioned processes.     

Differential effects of locally and systemically administered soluble glycoprotein 130 on pain and inflammation in experimental arthritis

Introduction  

Interleukin-6 (IL-6) is a key player in systemic arthritis, involved in inflammation and joint destruction. IL-6 signalling has also been revealed in nerve cells. Recently, IL-6 and in particular IL-6 together with its soluble IL-6 receptor (sIL-6R) were shown to induce a long-lasting robust sensitization of joint nociceptors for mechanical stimuli which was difficult to reverse, suggesting that IL-6 signalling plays a significant role in the generation and maintenance of arthritic pain. Here we tested in a preclinical model of arthritis, antigen-induced arthritis (AIA) in the rat, whether systemic or local neutralization of IL-6/sIL-6R complexes with soluble glycoprotein 130 (sgp130) alters arthritic pain and how sgp130 influences the inflammatory process in AIA.