Accuri C6 Flow Cytometer System
Originally published online as doi:10.1189/jlb.1105674 on May 17, 2006

Published online before print May 17, 2006
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(Journal of Leukocyte Biology. 2006;80:227-236.)
© 2006 by Society for Leukocyte Biology

Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer

Stefan Rose-John*,1, Jürgen Scheller*, Greg Elson{dagger} and Simon A. Jones{ddagger}

* Biochemisches Institut, Christian-Albrechts-Universität zu Kiel, Germany;
{dagger} NovImmune SA, Geneva, Switzerland; and
{ddagger} Department of Medical Biochemistry and Immunology, The School of Medicine Cardiff University, Wales, United Kingdom

1Correspondence: Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstr. 40, D-24098 Kiel, Germany. E-mail: rosejohn{at}biochem.uni-kiel.de

ABSTRACT

Cytokine receptors, which exist in membrane-bound and soluble forms, bind their ligands with comparable affinity. Although most soluble receptors are antagonists and compete with their membrane-associated counterparts for the ligands, certain soluble receptors are agonists. In these cases, complexes of ligand and soluble receptor bind on target cells to second receptor subunits and initiate intracellular signaling. The soluble receptors of the interleukin (IL)-6 family of cytokines (sIL-6R, sIL-11R, soluble ciliary neurotrophic factor receptor) are agonists capable of transmitting signals through interaction with the universal signal-transducing receptor for all IL-6 family cytokines, gp130. In vivo, the IL-6/sIL-6R complex stimulates several types of cells, which are unresponsive to IL-6 alone, as they do not express the membrane IL-6R. We have named this process trans-signaling. The generation of soluble cytokine receptors occurs via two distinct mechanisms—limited proteolysis and translation—from differentially spliced mRNA. We have demonstrated that a soluble form of the IL-6 family signaling receptor subunit gp130, which is generated by differential splicing, is the natural inhibitor of IL-6 trans-signaling responses. We have shown that in many chronic inflammatory diseases, including chronic inflammatory bowel disease, peritonitis, rheumatoid arthritis, asthma, as well as colon cancer, IL-6 trans-signaling is critically involved in the maintenance of a disease state, by promoting transition from acute to chronic inflammation. Moreover, in all these models, the course of the disease can be disrupted by specifically interfering with IL-6 trans-signaling using the soluble gp130 protein. The pathophysiological mechanisms by which the IL-6/sIL-6R complex regulates the inflammatory state are discussed.

Key Words: cytokine • cytokine receptor • gp130 • sgp130Fc fusion protein

INTRODUCTION

Cytokines of the interleukin-6 (IL-6) family act via receptor complexes containing at least one subunit of the signal-transducing protein gp130 [1 ]. The family comprises IL-6, IL-11, ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1), cardiotrophin-like cytokine (CLC), leukemia inhibitory factor (LIF), neuropoietin (NPN), and oncostatin M (OSM) [1 , 2 ] and has recently been supplemented by the addition of two newly characterized cytokines IL-27 and IL-31 [3 , 4 ]. IL-6, IL-11, and CNTF first bind to specific receptors, and these complexes associate with a homodimer of gp130 in the case of IL-6 and IL-11 or alternatively, with a heterodimer of gp130 and the related protein LIF receptor (LIF-R) in the case of CNTF, CLC, and NPN. OSM and LIF first bind directly to gp130 and LIF-R, respectively, and form heterodimers with LIF-R and gp130. In addition to signaling via a LIF-R/gp130 heterodimer, OSM can bind a gp130-related receptor (OSM-Rß), which again, heterodimerizes with gp130 to trigger OSM-mediated events [5 ]. This alternative OSM-R also interacts with an IL-31-binding protein to form an IL-31-specific receptor complex [3 ]. CT-1 binds directly to the LIF-R and induces gp130/LIF-R heterodimer formation [6 ], and the presence of an additional glycosylphosphatidylinositol-anchored receptor specific for CT-1 on neural cells has been hypothesized recently [6 ].

On target cells, IL-6 first binds to the IL-6 receptor (IL-6R). The complex of IL-6 and IL-6R associates with the signal-transducing membrane protein gp130, thereby promoting its dimerization and the subsequent initiation of intracellular signaling [1 , 7 ]. gp130 is expressed by most, if not all, cells in the body, whereas IL-6R is mainly expressed by hepatocytes, neutrophils, monocytes/macrophages, and some lymphocytes. A naturally occurring, soluble form of the IL-6R (sIL-6R), which has been found in various body fluids, is generated by two independent mechanisms: limited proteolysis of the membrane protein and translation from an alternatively spliced mRNA [8 9 10 11 12 13 14 15 ]. It is interesting that sIL-6R together with IL-6 stimulate cells, which only express gp130 [16 , 17 ], a process that is now termed trans-signaling [16 17 18 ] (Fig. 1A ).


Figure 1
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  		Figure 1. The IL-6R complex, trans-signaling, and the inhibitory mechanism of soluble gp130 (sgp130). (A) The two modes of IL-6 activation are presented as classical IL-6 activation via the membrane-bound IL-6R and sIL-6R-mediated cell signaling (IL-6 trans-signaling). In both cases, responses are elicited through engagement with membrane-bound gp130. (B) Classical IL-6 signaling is unaffected by sgp130 yet preferentially binds the IL-6/sIL-6R complex to antagonize IL-6 trans-signaling.

Recently, it has been shown that the sIL-6R strongly sensitizes target cells [19 ]. Embryonic stem cells [20 , 21 ], early hematopoietic progenitor cells [22 23 24 25 26 ], T cells [27 28 29 ], many neural cells [30 , 31 ], smooth muscle cells [32 ], mesothelial cells [33 , 34 ], and endothelial cells [35 ], among others, are only responsive to IL-6 in the presence of sIL-6R [18 ]. The fact that IL-6/sIL-6R promotes wound healing strongly argues that keratinocytes may also be subject to trans-signaling processes [36 ].

It is interesting that we recently showed that CNTF not only acts via the membrane-bound or soluble CNTF-R (sCNTF-R) but can elicit responses through direct binding to membrane-bound and sIL-6R [37 ]. This may have important implications for the use of CNTF as a therapeutic agent in neurodegenerative diseases [38 ] and for the treatment of obesity [39 ]. The use of CNTF as a drug in amytrophic lateral sklerosis had to be discontinued as a result of severe peripheral side-effects. This was surprising, as the CNTF-R is not widely expressed outside of the central nervous system. The fact that CNTF can also signal via the IL-6R may explain most if not all of these side-effects and will be the basis for the construction of CNTF variants, which only bind to the CNTF-R but not to the IL-6R [37 ].

THE CONCEPT OF DESIGNER CYTOKINES

Using the structural information available on membrane-bound and soluble cytokine receptors, we have constructed chimeric proteins in which receptor recognition modules have been altered or exchanged and/or in which cytokines have been fused to their soluble cytokine receptors. Furthermore, chimeric receptor proteins have been constructed, which contain cytokine-binding modules of gp130, LIF-R, or OSM-Rß. This approach has allowed the definition of cytokine-binding modules on receptor proteins [40 41 42 43 44 ].

We have also constructed a fusion protein consisting of the domains of IL-6 and sIL-6R, which are necessary for biological activity. The engineering of this chimeric protein has been performed through covalently linking the two functional proteins via a flexible polypeptide linker. The resulting recombinant protein was found to be 100–1000 times more active than the native IL-6/sIL-6R complex and as a result of this enhanced activity, was termed Hyper-IL-6 [45 ]. Many cells, including hematopoietic progenitor cells, neuronal cells, endothelial cells, smooth muscle cells, and embryonic stem cells, which do not respond to IL-6 alone, show a remarkable response to IL-6/sIL-6R [18 , 21 , 25 , 45 46 47 48 ]. Recently, our approach has been adopted to construct a fusion protein between IL-11 and sIL-11R [49 ]. A designer cytokine consisting of CNTF or CLC, fused to the sCNTF-R, has also been constructed, and these unimolecular proteins exhibit high neurotrophic activity on cells negative for surface CNTF-R expression [47 , 50 ].

THE PHYSIOLOGIC ROLE OF sgp130

We have analyzed the role of sgp130 using a recombinant sgp130 protein fused to the Fc region of human immunogloblin G1 [51 ]. The sgp130 protein only inhibited the expression of the acute-phase protein antichymotrypsin in HepG2 cells, which had been treated with Hyper-IL-6, whereas IL-6-stimulated HepG2 cells remained unaffected. It turned out that sgp130 exclusively inhibited IL-6 responses mediated by the sIL-6R without interfering with responses via the membrane-bound IL-6R. sgp130 has been shown to modulate leukocyte trafficking and to suppress the severity of experimental arthritis, colitis, and colon cancer [27 , 28 , 33 , 52 , 53 ]. Indeed, the phenotype of the response exhibited in vivo following sgp130 administration often closely resembles those observed in IL-6-deficient mice. Therefore, we postulated that sgp130 acts as the natural inhibitor of IL-6/sIL-6R complexes. In this respect, IL-6 does not bind sgp130 directly, and consequently, it is proposed that classical IL-6 via the cognate IL-6R and membrane-bound gp130 remain unhindered. Our model of the molecular mechanism by which sgp130 exerts selective inhibition toward the IL-6/sIL-6R complex is depicted in Figure 1B . Kinetic appraisal of binding parameters suggest that the IL-6/sIL-6R complex has equal affinity for membrane-bound and sgp130 variants, and therefore, a molar excess of sgp130 leads to inhibition of IL-6 trans-signaling [18 , 54 ]. The pathophysiological consequence of this selective inhibition is outlined below.

sgp130 SPECIFICALLY INHIBITS IL-6 TRANS-SIGNALING

As gp130 is the common receptor subunit of the cytokines IL-6, IL-11, IL-27, CLC, CNTF, CT-1, LIF, OSM, and NPN, it is reasonable to question whether inhibition by sgp130 is specific for the IL-6/sIL-6R complex or whether sgp130 also affects the biologic activity of the other gp130 family cytokines. We have shown that the activity of CNTF is unaffected by the sgp130Fc protein. The proliferative activity of LIF and OSM on BAF/3 cells stably transfected with gp130 and LIF-R cDNAs is only inhibited by more than 100-fold higher sgp130Fc concentrations than those needed to inhibit Hyper-IL-6 [51 , 55 ]. This wascorroborated by surface plasmon resonance, which shows that Hyper-IL-6 and OSM bind sgp130 with dissociation constant values of 6.9 x 10–9 M and 1.6 x 10–7 M, respectively [56 ]. The cytokine IL-27 has recently been found to act via a receptor complex consisting of gp130 and the related receptor protein WSX-1 [4 ]. We therefore addressed the question of whether sgp130Fc exhibited an inhibitory effect on the activity of IL-27. We could clearly show that the sgp130Fc protein did not affect the IL-27-mediated signal transducer and activator of transcription 3 (STAT3) phosphorylation and proliferation of BAF/3 cells expressing gp130 and WSX-1 [55 ]. We concluded from these results that the sgp130Fc protein specifically inhibits the IL-6/sIL-6R trans-signaling responses [55 ].

DEFINING AN INFLAMMATORY CONTEXT FOR IL-6 TRANS-SIGNALING

Recent advances have documented a series of IL-6 activities, which are critical for resolving innate immunity and promoting acquired immunity [57 ]. Transition between innate and acquired immunity is a central event in the resolution of any inflammatory condition, and disruption of this immunological switch may potentially distort the immune response and affect the onset of autoimmune or chronic inflammatory disorders [58 ]. Such distortion of the immunological response may provide a viable mechanism to explain the previously documented role that IL-6 performs in governing chronic disease progression [59 ].

By placing IL-6 trans-signaling within this inflammatory context, studies are now beginning to comprehend how IL-6 protects against septic shock and directs resolution of acute inflammation and conversely, elicits detrimental consequences in more progressive chronic diseases [60 61 62 63 64 65 ]. Rationalization of these IL-6 activities has been aided by advances in our understanding of the physiological contribution of IL-6 trans-signaling [27 , 33 , 52 , 66 , 67 ] and by the observed interplay between IL-6 signaling and STAT1, interferon-{gamma}, transforming growth factor-ß (TGF-ß), GATA-3, and nuclear factor (NF)-{kappa}B [28 , 34 , 53 , 68 69 70 ]. Such interactions appear to influence disease outcome significantly and have been implicated in the resolution of acute inflammation, asthma, tumor expansion, and the inflammatory response associated with tumor progression [28 , 33 , 53 , 67 ]. A common feature arising amongst all of these studies is the role IL-6 trans-signaling performs in orchestrating leukocyte recruitment, activation, and apoptotic clearance [57 ].

Through modulation of inflammatory chemokine expression and apoptotic control processes, it is evident that IL-6 suppresses neutrophil infiltration and concurrently promotes the attraction and activation of mononuclear leukocytes [27 , 28 , 33 , 34 , 52 , 53 , 66 67 68 69 , 71 72 73 ]. Consequently, IL-6 governs the resolution of acute innate immunity and steers transition to an acquired immune response [57 ]. The significance of this activity is borne out in experimental models of colitis and rheumatoid arthritis, where blockade of sIL-6R-mediated events leads to improved disease outcome by affecting the recruitment or apoptotic clearance of mononuclear cells [27 , 52 ]. Retention of an activated mononuclear cell population within inflamed tissue represents a clinical feature of chronic disease progression, and these studies suggest that IL-6 trans-signaling may contribute to this hallmark of disease. Credence for this notion is provided by a series of in vitro and in vivo studies, which have shown IL-6 to rescue T cells from apoptosis through the STAT3-mediated induction of antiapoptotic regulators [27 , 68 , 74 75 76 77 78 79 ]. Significant attention has therefore been given to the IL-6-mediated control of this activated mononuclear cell population [57 ].

Through the analysis of mononuclear cell infiltration in wild-type and IL-6–/– mice, it is evident that IL-6 directs T cell recruitment by regulating local chemokine secretion [CXC chemokine ligand 10, CC chemokine ligand 2 (CCL2), CCL4, CCL5, CCL11, CCL17)] and chemokine receptor [CC chemokine receptor 3 (CCR3), CCR4, CCR5, CXC chemokine receptor 3] expression on the CD3+ infiltrate [33 , 67 ]. Documentation of these activities has been aided by the selective antagonism of IL-6 trans-signaling in vivo by sgp130 [51 ], which thus enables responses governed by IL-6 trans-signaling to be clearly distinguished from those of IL-6 itself. In this respect, sgp130 blocked chemokine expression selectively but did not affect T cell chemokine receptor expression [67 ]. A similar scenario was also reported in experimental asthma, where IL-6 was shown to direct T helper cell type 2 (Th2) polarization, and Th2-type responses required IL-6 trans-signaling [53 ]. Consequently, IL-6 influences T cell responses directly and in conjunction with its soluble receptor. Such insight leads us to question whether T cells universally express a cognate IL-6R or if it defines a specific T cell subset. Comparative analysis of CD3+ T cells from the circulation and at sites of inflammatory challenge shows that although 35–45% of circulating T cells express IL-6R, only 2–5% of the CD3+ infiltrate are IL-6R+ [27 , 28 , 79 ]. Thus, inflammation results in a selective down-regulation in IL-6R expression or the homing of a CD3+IL-6R– T cell subset to inflammatory foci. These defined subsets may represent differences in activation status, as T cells challenged in vivo with superantigen show significantly lower levels of IL-6R [76 ]. Significantly, much debate has focused on whether IL-6 drives differentiation toward a Th1- or Th2-restricted phenotype [78 , 80 81 82 83 84 85 ]. However, the presence of a cognate IL-6R on Th1 and Th2 cells suggests that IL-6 provides a more generalized function [81 ].

The IL-6-mediated control of cellular differentiation is also important in the polarization of monocytic cells. Specifically, IL-6 directs human monocytes away from a dendritic lineage to a macrophage phenotype [86 , 87 ]. Such skewing of monocytic differentiation is also evident in vivo, where expansion of bone marrow-derived dendritic cells (DC) from IL-6–/– mice results in a tenfold higher number of CD11c+ DC than in IL-6+/+ mice [88 ]. However, the activity of these expanded cells is impaired, suggesting that IL-6 secretion by these cells may be necessary for their own activity [88 ]. Indeed, IL-6 has been shown to inhibit NF-{kappa}B activity and to suppress CCR7 expression in DC [70 ], and IL-6 secretion by DC following Toll-like receptor activation blocks the immunosuppressive activities of regulatory T cells (Treg) [89 ]. Thus, IL-6 may influence DC maturation or trafficking and may be critical in advancing adaptive immune responses [70 , 89 ].

Overall, these studies have highlighted roles for IL-6 in innate and acquired immune responses and suggest that inappropriate control of these events may contribute to chronic disease progression. However, with the emergence of IL-6 trans-signaling as an alternative mode of IL-6 activation, it has become increasingly apparent that selective targeting of sIL-6R-mediated events may represent a novel avenue for therapeutic intervention (Fig. 2 ).


Figure 2
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  		Figure 2. Therapeutic strategies for targeting IL-6 signaling. Current therapeutic regimes designed to clinically suppress IL-6 activities involve the application of blocking monoclonal antibodies (mAb). In particular, Atlizumab/Tocilizumab (MRA) has proven in clinical trials to be effective against a range of conditions. Such approaches, however, do not delineate between classical IL-6 signaling via its cognate receptor and IL-6 trans-signaling. This regime, therefore, offers a global blockade of IL-6 bioactivity. The natural antagonist sgp130 selectively targets IL-6 trans-signaling and in essence, should leave classical IL-6 signaling intact. This approach influences a variety of immunological processes and through recent studies, suggests that not all IL-6-mediated events are disturbed by its action. PM, plasma membrane.

IL-6 TRANS-SIGNALING IN ARTHRITIS: A RATIONALE FOR POTENTIAL THERAPEUTIC INTERVENTION

Early diagnosis and treatment of rheumatoid arthritis substantially improve disease prognosis and suggest that a targeted management of initial inflammatory processes is therapeutically advantageous [90 ]. Conceptually, this is exemplified by the selective blockade of inflammatory cytokines, which through the introduction of novel biologics such as anti-tumor necrosis factor-{alpha} (TNF-{alpha}) agents, has led to considerable clinical benefit [90 ]. Although this approach has validated the targeting of inflammatory cytokines as a strategy for treating ongoing rheumatoid arthritis, the long-term safety and efficacy of such therapeutic agents remain uncertain. Indeed, the increased association of active tuberculosis with anti-TNF-{alpha} therapy and the inability of certain individuals to respond to such regimes have highlighted the necessity to identify alternative strategies for the management of chronic arthritis.

One factor that has recently received closer inspection is IL-6. Collective studies have emphasized a central role for IL-6 in governing inflammation and highlight the therapeutic potential of targeting IL-6 as a strategy for the treatment of chronic inflammatory diseases. It is significant that IL-6-deficient (IL-6–/–) mice remain resistant to the induction of a number of experimental autoimmune conditions [52 , 60 , 85 , 91 , 92 ], and agents that inhibit IL-6 or its receptor have shown considerable promise in Phase I and II clinical trials [93 94 95 96 97 ]. Indeed, the blocking anti-IL-6R antibody MRA (Atlizumab) is highly effective in the management of rheumatoid arthritis and Crohn’s disease and appears well-tolerated with no adverse reports of infection or toxicity [93 , 94 ]. Results from these trials not only show improved disease activity but highlight that MRA reduces the necessity for supplementary anti-inflammatory agents (corticosteroids or disease-modifying antirheumatic drugs) and also remains the only anticytokine therapy currently under clinical investigation, which normalizes levels of acute-phase reactants in patients with active disease [93 , 94 ]. This infers that an alteration in IL-6 signaling exacerbates inflammation and perpetuates chronic disease progression. However, it is unclear whether blockade of IL-6 bioactivity offers a true advantage over anti-TNF-{alpha} agents, raising the possibility of combination therapies for selected patient cohorts. To substantiate such a concept, however, it is essential to understand how in some cases, cytokines, such as IL-6, direct the inflammatory response to ensure successful resolution of a disease process, and in others, they perpetuate transition to a chronic, inflammatory state.

First indications that IL-6 may have a profound influence on arthritis progression are derived from the documentation of extremely high IL-6 concentrations within the serum and synovial fluids of rheumatoid arthritis and juvenile rheumatoid arthritis patients [98 99 100 101 ]. Such changes infer that IL-6 may affect systemic events such as high fever, autoantibody production, and expression of acute-phase reactants, and localized increases within the inflamed joint suggest its involvement in joint pathology [102 , 103 ]. Indeed, a series of in vivo studies using models of experimental arthritis have now endorsed roles of IL-6 in joint destruction, leukocyte recruitment, apoptosis, and T cell activation with IL-6-deficient (IL-6–/–) mice, showing limited or no pathological signs of disease [52 , 85 , 92 , 104 105 106 107 108 ]. It is significant that the highly protected phenotype exhibited by IL-6–/– mice is not common to all gp130-activating cytokines, as OSM-Rß- and IL-11R-deficient strains develop arthritis and show no histological differences compared with wild-type mice [108 ]. Such findings indicate that the gp130-mediated responses elicited by IL-6 are unique, and although blockade of IL-6 signaling is clinically advantageous in the treatment of rheumatoid arthritis [93 , 95 96 97 ], enhanced IL-11 activities appear to suppress arthritis progression [109 , 110 ]. At present, the signaling mechanisms distinguishing these distinct clinical outcomes remain unclear.

Although IL-6 is considered to play a detrimental role in arthritis progression, structural cells of the joint (chondrocytes, synoviocytes, fibroblasts, endothelial cells) lack expression of a functional, cognate IL-6R [52 , 102 ]. This has highlighted the necessity to understand the regulation of IL-6-mediated events and the impact of sIL-6R on arthritic lesions. Elevated sIL-6R levels have been documented in rheumatoid arthritis and juvenile rheumatoid arthritis [52 , 102 , 111 112 113 ], where the highest levels of sIL-6R and IL-6 are associated with the more progressive incidences of disease [113 ]. In this respect, elevated IL-6 and sIL-6R concentrations have been reported tocorrelate with the degree of joint destruction typically observed in rheumatoid arthritis [111 ]. Indeed, synovial fluids from rheumatoid arthritis patients containing high levels of IL-6 and sIL-6R promote osteoclast-like cell formation when added to cocultures of osteoblastic cells and bone marrow cells [111 ]. A role for sIL-6R in bone matrix catabolism is supported further by the observation that IL-6 trans-signaling promotes collagenase-3 release in osteoblasts and proteoglycan synthesis in chondrocytes and cartilage explants [114 115 116 ]. Taken together, these findings indicate that sIL-6R contributes, at least in part, to joint destruction.

The presence of elevated sIL-6R levels in arthritic episodes strongly suggests that sIL-6R production is coordinated as part of the inflammatory response. Through comparison of sIL-6R determinations in serum and synovial fluid of patients with rheumatoid arthritis, it is difficult to judge whether the elevated sIL-6R levels associated with this disease are derived from systemic or local sources [102 ]. However, it is conceivable that the source of synovial sIL-6R may be derived from activated leukocytes [33 ]. This may account for the observedcorrelation between leukocyte influx into arthritic joints and the increased concentration of sIL-6R in synovial fluid [102 ]. It is significant that intra-articular administration of IL-6 itself is not sufficient to restore arthritis severity in IL-6–/– mice primed for antigen-induced arthritis and does not affect the degree of leukocyte influx into the joint [52 ]. Conversely, intra-articular reconstitution of IL-6 trans-signaling with Hyper-IL-6 promotes the infiltration of CCR2+ mononuclear leukocytes and a concurrent increase in joint pathology [52 ]. Thus, regulation of synovial sIL-6R may represent the rate-limiting step in the development of joint pathology. It must be stressed, however, that systemic sIL-6R production may also contribute to the regulation of IL-6 responses in arthritis, as sIL-6R levels are elevated significantly in systemic onset juvenile chronic arthritis [112 ].

Such insight has led us to consider whether preferential targeting of IL-6 trans-signaling may represent a viable alternative strategy for the treatment of rheumatoid arthritis and other chronic inflammatory disorders [27 , 28 , 33 , 52 , 53 , 67 ]. For this purpose, we have elected to use the selective antagonistic properties of the naturally occurring sgp130 [51 ]. As a strategy, this offers a number of clear advantages, as administration of sgp130 can be used to supplement the existing, circulating levels seen within all individuals and will not result in a global blockade of all IL-6 responses, which may have more widespread clinical ramifications. The rationale for this approach is borne out from the clinical analysis of synovial IL-6, sIL-6R, and sgp130 levels in rheumatoid arthritis and osteoarthritis patients [56 ]. Although IL-6 and sIL-6R concentrations were elevated significantly in individuals with rheumatoid arthritis, sgp130 levels remained unaltered in both patient cohorts, suggesting that the regulation of IL-6 trans-signaling may be distorted in rheumatoid arthritis. To substantiate the validity of this approach, studies exploiting a monoarticular antigen-induced model of arthritis were adopted [52 , 56 ]. Specifically, histological analysis of joint sections from IL-6+/+ mice treated with an intra-articular dose of sgp130 showed that all parameters of disease severity (leukocyte infiltration, synovial hyperplasia, joint erosion, and CCL2 expression) were suppressed as a result of sgp130 administration [52 ]. Indeed, no significant difference was observed between the histological scores attributed to IL-6–/– mice and those assigned to IL-6+/+ mice exposed to sgp130. It is significant that several isoforms of sgp130 have been described [18 ]. One form, known as gp130-rheumatoid arthritis antigenic peptide-bearing soluble form (RAPS), has been defined as a rheumatoid arthritis autoantigen with serum antibodies against gp130-RAPS,correlating with indices of disease activity [117 ]. Although the increased incidence of autoantibodies against gp130-RAPS could not be substantiated in a Caucasian rheumatoid arthritis population, this highly truncated sgp130-spliced variant was found to be highly efficient at blocking joint pathology and STAT3 activation in antigen-induced arthritis [56 ]. Although the significance of these findings needs to be clarified in more advanced, systemic models of arthritis, sgp130 may symbolize a valuable addition to the current arsenal of therapeutics proven to be effective in the management of chronic conditions such as rheumatoid arthritis.

MEMBRANE-BOUND AND sIL-6R IN ASTHMA

IL-6 is known to be secreted by cells mediating the innate immune response. Also, IL-6 induces the expansion of Th cells, which are a major component of the acquired immune response [118 ]. In addition, IL-6 has been shown to be secreted by activated DC and to suppress the activity of Treg cells leading to peripheral tolerance [89 ]. In view of these results, it was reasonable to investigate the role IL-6 plays in the development of asthma. Increased levels of sIL-6R in the airways of patients with allergic asthma compared with those in controls have been observed [53 ]. It is interesting that it turned out that the proliferation of mucosal Th2 cells depends on IL-6 trans-signaling via the sIL-6R, whereas the suppression of Treg cells and the initial stages of Th2 cell development in the lung depends on gp130 signals mediated by the membrane-bound IL-6R [53 ]. This wascorroborated by the fact that CD4+CD25+ but not CD4+CD25– lung T cells selectively expressed the IL-6R and showed IL-6-dependent STAT3 phosphorylation. Therefore, one can predict that the treatment of asthma patients with the sgp130Fc protein would reduce Th2 cells in the lung and that blockade of the membrane-bound IL-6R by the neutralizing antibody MRA [119 ] would increase the number of Treg cells in the lung, thereby reducing the local number of CD4+ T-effector cells [118 ].

IL-6 TRANS-SIGNALING IN COLITIS AND COLON CANCER

We have previously demonstrated a functional role for sIL-6R in chronic inflammatory bowl disease (Crohn’s disease) [27 ]. We have shown that T cells from gastric tissue of Crohn’s disease patients are extremely resistant to apoptosis and show activation of the Janus tyrosine kinase-STAT signal transduction pathway. These T cells produce large amounts of IL-6 but lack membrane-bound IL-6R. It is surprising that treatment of these cells with a neutralizing mAb to IL-6R induced apoptosis. Moreover, treatment of the cells with sgp130 showed the same effect (Fig. 3 ). These results demonstrate that IL-6 trans-signaling promotes retention of activated T cells within gastric tissue from Crohn’s disease patients and is facilitated through the induction of antiapoptotic regulators. IL-6R shedding is therefore an active process within this condition, and sIL-6R required for IL-6-dependent gp130 activation is most likely released by LPMC macrophages or infiltrating neutrophils [27 , 51 ]. It is interesting that it was recently reported that not only levels of IL-6 but also levels of sIL-6R and sgp130 are elevated in chronic inflammatory bowel diseases and that IL-6 found in the circulation was complexed to sIL-6R and sgp130 [120 ].


Figure 3
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  		Figure 3. Apoptosis of lamina propria mononuclear cells (LPMC) of Crohn’s disease patients upon treatment with sgp130. LPMC were isolated and cultured for 48 h in the presence or absence of 10 µg/ml of a neutralizing mAb specific for human IL-6R or 10 µg/ml sgp130Fc. Subsequently, cells were stained for annexin V and propidium iodide (PI) and analyzed by fluorescein-activated cell sorter. The increase in apoptotic (annexin V-positive and PI-negative) cells is shown. The data presented are means of triplicate measurements with standard errors shown as vertical bars.

In an inflammatory colon cancer model, we could also demonstrate that there is cross-talk between the cytokine TGF-ß and IL-6 (Fig. 4 ). Using TGF-ß transgenic mice and T cell-specific TGF-ßR dominant-negative mice, we could show in this inflammatory model that reduced stimulation of T cells by TGF-ß resulted in an increase in IL-6 production by these T cells. It is surprising that we detected a loss of membrane-bound IL-6R from the cell surface of epithelial cells in tumor lesions, which was accompanied by an increase of cell surface expression of the protease ADAM17, responsible for cleavage of the IL-6R [14 ]. Tumor growth could not only be inhibited by a neutralizing antibody directed against the IL-6R but also by sgp130Fc, strongly arguing that the growth of the tumor was regulated by IL-6 trans-signaling rather than by classic signaling via the membrane-bound IL-6R [28 , 29 ]. It is intriguing that in human colon cancer patients, a similar down-regulation of IL-6R and up-regulation of ADAM17 on the surface of tumor epithelial cells were observed, implying that a similar mechanism is operating in human and mouse colon cancer development [29 ]. We therefore argue that interrupting IL-6 trans-signaling with sgp130Fc will be a promising strategy for the treatment of colon cancer in humans.


Figure 4
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  		Figure 4. Schematic model of TGF-ß-regulated IL-6 trans-signaling in experimental colon cancer. (A) A reduction of TGF-ß signaling results in increased IL-6 secretion. (B) The observed up-regulation of a disintegrin and metalloproteinase 17 (ADAM17) on epithelial cells results in shedding of IL-6R. T cells, upon stimulation with the IL-6/sIL-6R complex, become resistant to apoptosis, and therefore, the number of T cells increases. (C) Growth of epithelial cells in tumor lesions is observed upon stimulation with the IL-6/sIL-6R complex. Tumor growth can be inhibited by blocking the IL-6R using a mAb and by inhibiting IL-6 trans-signaling with the sgp130Fc protein. Green symbols, gp130; light red symbols, IL-6; dark red symbols, membrane-bound IL-6R and sIL-6R; blue symbols, epithelial cells.

FUTURE PERSPECTIVES

We conclude that sgp130 is the natural inhibitor of sIL-6R-dependent IL-6 responses. The selective antagonistic properties of sgp130 can therefore be used in vivo to delineate between classical IL-6 signaling and IL-6 trans-signaling. Using this strategy, it is increasingly evident that sgp130 is effective in blocking immunological processes, which promote inflammatory disease progression. Such advances have provided a therapeutic rationale for the administration of sgp130 in a series of chronic inflammatory and autoimmune conditions.

ACKNOWLEDGEMENTS

The work in the laboratory of S. R-J. and J. S. was supported by grants from the Deutsche Forschungsgemeinschaft Bonn (Germany), and the Wellcome Trust and the Arthritis Research Campaign supported the work of S. A. J.

Received November 17, 2005; revised April 9, 2006; accepted April 19, 2006.

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