SurveyIL-6 in autoimmune disease and chronic inflammatory proliferative disease
Introduction
Interleukin 6 (IL-6) was originally identified as a B-cell differentiation factor [1], [2], but it is now known to be a multifunctional cytokine that regulates the immune response, hematopoiesis, the acute phase response, and inflammation [3]. IL-6 is a cytokine with a helical structure that is similar to many other cytokines [1], [4]. The IL-6 receptor (R) and many other cytokine receptors are structurally similar and constitute the cytokine receptor super family [5], [6], [7]. In addition, cytokine receptor subunits are shared among several cytokine receptors [8], [9], [10], [11], [12], [13]. This sharing of subunits is one of the mechanisms through which the functional redundancy of cytokine activities occurs. The IL-6 receptor system consists of two molecules, IL-6Rα and gp130, the latter of which is shared among the receptors for IL-6, leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), oncostatin M (OSM), IL-11, and cardiotrophin-1 (CT-1) [14].
IL-6 stimulation activates JAK tyrosine kinases, which are constitutively associated with gp130, leading to the induction of two major signal transduction pathways through the cytoplasmic domain of gp130: the SHP-2/GAB-mediated ERK MAPK pathway and the STAT3-mediated pathway [14], [15]. The former is dependent on tyrosine 759 (Y759) of gp130 and the latter requires any one of Y767, Y814, Y904, and Y915, which are all in the YXXQ motif context. An in vivo study using knock-in mice expressing a mutant gp130 defective in either the Y759-dependent signal (SHP-2 signal) or the YXXQ-dependent signals (STAT3 signals) clearly showed that the Y759-mediated signal is required for gp130-mediated ERK MAPK activation, but not for mouse survival, whereas the YXXQ-dependent signals, most likely the STAT3 signals, are required for mouse neonate survival [16]. In addition, the Y759-dependent signal is involved in the defense response against Listeria monocytogenes infection [17], while the YXXQ-dependent signal is required for the acute phase reaction, IgG2a and IgG2b production, Th1 type cytokine production, and B-cell differentiation [16]. The most interesting finding is that Y759 negatively regulates gp130-mediated signals, in particular the STAT3-mediated signals. These results indicate that the balance between a variety of signals generated through a given cytokine receptor, for example gp130, is critical to the determination of the final biological output generated by a given cytokine [14], [18]. This concept may be important in considering the mechanisms by which a given cytokine plays a role in health and disease.
The first suggestion that IL-6 is involved in autoimmunity came from the findings that cardiac myxoma cells produce IL-6 and that patients with cardiac myxoma frequently show autoimmune symptoms [19]. Furthermore, synovial fluids obtained from patients with rheumatoid arthritis (RA) were found to contain elevated amounts of IL-6 [20]. Since then, several pieces of evidence have been reported that suggest the involvement of IL-6 in autoimmune diseases, chronic inflammatory proliferative disease (CIPD), and B-cell malignancy, including systemic lupus erythematosus (SLE), Castleman’s disease, and plasmacytoma/multiple myeloma [3]. Furthermore, IL-6 is required for experimentally induced autoimmune diseases and autoimmunity, including type II collagen- and antigen-induced arthritis (CIA and AIA) [21], [22], [23], myelin oligodendrocyte protein-induced experimental autoimmune encephalomyelitis (EAE) [24], [25], and pristane-induced autoantibody production [26]. These results, together with accumulating evidence obtained from a large body of clinical studies, suggest that IL-6-dependent signaling pathways are involved in the pathogenesis of these experimentally induced autoimmune diseases as well as of naturally occurring autoimmune diseases, although it is unknown how and at what levels IL-6 plays its roles in the complex processes of these diseases. Here we discuss the possible roles of IL-6 in autoimmune diseases and CIPD.
Section snippets
IL-6 and chronic inflammation: its implication in polyclonal B-cell activation and autoantibody production
Cardiac myxoma is a benign intraatrial heart tumor, and one-third of the patients with cardiac myxoma show autoimmune symptoms such as hypergammaglobulinemia and the production of autoantibodies [19]. These symptoms disappear upon surgical removal of the tumor, suggesting that the myxoma itself or its products are involved in the autoimmune condition of these patients. In fact, culture supernatants of these tumor cells were found to contain high IL-6 activity, and IL-6 mRNA was detected in
Overexpression of IL-6 results in the generation of polyclonal plasmacytosis and malignant plasmacytoma
Mice expressing IL-6 as a transgene (IL-6 transgenic mice) develop a massive polyclonal plasmacytosis with autoantibody production and mesangial cell proliferative glomerulonephritis that resembles the autoimmune diseases observed in NZB/W F1 mice or SLE patients [67]. The development of hypergammaglobulinemia has also been reported in mice whose bone marrow has been altered by the transplantation of cells infected with a retroviral vector expressing murine IL-6 [68].
Plasma cells generated in
Insulin-dependent diabetes mellitus and IL-6
Several pieces of evidence support a role for IL-6 in the diabetes developed by the nonobese diabetic (NOD) mouse, an animal model for insulin-dependent diabetes mellitus (IDDM). IL-6 production is first detected in the pancreas at 10 weeks of age and disappears by 16 weeks in both NOD and BALB/c mice. It is also present in the endothelial cells [73]. IL-6 production by the cells that infiltrate the Langerhans’ islets and in the endocrine islet of NOD females is found at all ages [74]. β-cell
Inflammatory bowel disease and IL-6
Serum IL-6 concentrations are significantly higher in patients with Crohn’s disease (CD) than in patients with ulcerative colitis (UC) and healthy controls [80], [81]. In individual patients, serum IL-6 levels correlate with the corresponding CD activity index in patients with a primarily inflammatory disease and without bowel stenosis, previous intestinal resection, or concomitant inflammatory disorders [82]. Longitudinally measured serum IL-6 levels reflect the patients’ clinical response
Experimental autoimmune encephalomyelitis and IL-6
Experimental autoimmune encephalomyelitis is induced by immunization with myelin components such as myelin oligodendrocyte glycoprotein (MOG) and is used as an animal model for a demyelinating disease, multiple sclerosis. Myelin-specific Th1 cells enter the CNS via the binding of very late antigen 4 (VLA-4), which they express, to the endothelial vascular cell adhesion molecule 1 (VCAM-1). IL-6-deficient mice are resistant to the MOG-induced EAE, compared with wild-type mice [24], [25], [93].
Rheumatoid arthritis and IL-6
RA is a heterogeneous, chronic joint disease that is characterized by leukocyte invasion and synoviocyte activation followed by cartilage and bone destruction [95]. It has properties of both autoimmune and chronic proliferative inflammatory diseases [3]. In the 1970s, B cells and their products were the preferred candidate effecter cells for RA [96]. The evidence supporting this idea was that RA is frequently associated with polyclonal B-cell activation, the production of autoantibodies, and
Polymorphisms in the human IL-6 gene
As described above, because several lines of evidence support the involvement of IL-6 in various autoimmune diseases, several groups have intensively examined the genetic polymorphisms related to these diseases. The human IL-6 gene is located on chromosome 7p21. The chromosome localizations of the IL-6 gene of mouse and rat are chromosomes 5 and 4, respectively. The human IL-6Rα gene is located on chromosome 1q21. The mouse and rat IL-6Rα genes are on chromosomes 3 and 2, respectively. The
Possible mechanisms
Because STAT3 activation is one of the prominent features of IL-6 stimulation, the activation state of STATs in samples of arthritic joints from patients or experimental models has been examined. STAT3 is strongly tyrosine phosphorylated in the synovial tissue of RA patients, but not of patients with osteoarthritis [126]. Furthermore, the mRNA for the endogenous cytokine signaling repressor CIS3/SOCS3 is abundantly expressed in RA patients. In murine experimental arthritis models, Shouda et al.
Conclusion and future prospects
IL-6 is a pleiotropic cytokine originally identified as a B-cell differentiation factor. Its excess activity in vivo results in polyclonal B-cell activation, plasmacytosis, and B-cell neoplasia. These changes provide a basis for autoantibody production. At the beginning of acute inflammation, IL-6 mediates the acute phase responses. When its activity as a pro-inflammatory cytokine persists, acute inflammation turns into chronic inflammation that includes immune responses. In the chronic phase
Acknowledgements
We thank our colleagues, who contributed to our recent studies described in this review. We also thank Ms. R. Masuda and A. Kubota for secretarial assistance. This work is supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology in Japan, and the Osaka Foundation for the Promotion of Clinical Immunology.
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