Joint disease caused by defective gp130-mediated STAT signaling
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IL-6 is a multifunctional cytokine produced by lymphoid and nonlymphoid cells; it regulates immune responses, acute-phase reactions, and inflammation. IL-6 signaling is mediated exclusively by the common signal-transducing component gp130, which is also essential for signal transduction of other cytokines of the leukemia inhibitory factor (LIF)/IL-6 family. M Ernst and colleagues generated and studied knock-in mice (gp130ΔSTAT/ΔSTAT), in which all STAT-binding sites (sites binding signal transducers and activators of transcription) were deleted from their gene encoding gp130 but binding sites for both Janus kinases (JAKs) and for the protein tyrosine phosphatase-2 (SHP-2) were preserved. They found that this mutant mouse displayed a blastocyst implantation defect, gastrointestinal ulceration, and, interestingly, severe joint disease with representative features of rheumatoid arthritis. Synovial cells from this mouse exhibited mitogenic hyper-responsiveness to cytokines of the LIF/IL-6 family, a phenomenon that was caused by sustained gp130-mediated SHP-2/Ras/Erk activation due to a defect in the induction of SOCS-1 (suppressor of cytokine signaling-1; also known as SSI or JAB). This suppressor, induced by STAT signaling, regulates cytokine signaling. It is, therefore, conceivable that the disturbance of the balanced activation between the STAT and SHP-2/Ras/Erk signal pathways causes the joint disease in the gp130ΔSTAT/ΔSTAT mouse. These findings may be beneficial in the elucidation of the cause and the treatment of rheumatoid arthritis in humans.
Keywordsgp130 interleukin-6 rheumatoid arthritis suppressor of cytokine signaling
= Janus kinase
= leukemia inhibitory factor
= mitogen-activated protein kinase
= rheumatoid arthritis
= tyrosine phosphatase-2
= suppressor of cytokine signaling
= signal transducer and activator of transcription.
Rheumatoid arthritis (RA) is a major immune-mediated human disease of unknown cause. Nevertheless, cumulative evidence suggests that cytokines are important mediators in its pathology . These substances, especially the so-called proinflammatory cytokines, such as IL-1, tumor necrosis factor-α, and IL-6, play a pivotal role in the pathology of RA. Recently, Ohshima et al. showed that IL-6 is essential for the development of antigen-induced arthritis, an experimental autoimmune arthritis model that resembles RA histologically . Furthermore, results of a recent clinical trial of anti-IL-6-receptor antibody therapy for RA support this idea  (reviewed in ). However, the molecular mechanisms by which IL-6 is involved in joint destruction in RA have not yet been identified. A detailed study of gp130ΔSTAT/ΔSTAT mice, in which gp130-mediated signal transducer and activator of transcription (STAT) signal was disrupted, showed that lack of STAT-mediated induction of SOCS-1 (suppressor of cytokine signaling-1) accelerates the SHP-2/Ras/Erk signal cascade that would be downregulated by SOCS-1 induction; the acceleration eventually resulted in severe joint disease .
gp130 signal cascades in IL-6
Joint disease in the gp130ΔSTAT/ΔSTAT mouse
gp130ΔSTAT/ΔSTAT mice, under specific, pathogen-free conditions, spontaneously exhibited swelling of one or more of the large, weight-bearing joints and flexion deformities of the bilateral hind legs . These changes occurred young and consistently progressed, albeit with various degrees of severity. The histological examination of clinically affected joints in young gp130ΔSTAT/ΔSTAT mice revealed enlargement of the synovial space, synovial hyperplasia and pannus formation, cartilaginous overgrowth in the menisci, and destruction and deformation of the articular surfaces. In addition, the knee joints of older mutant mice showed destruction and erosion of the articular cartilage as well as expansion of the synovial space. Later, inflammatory cells, mostly lymphocytes and macrophages, were found in the synovium and subsynovial tissues of the diseased joints. Taken together, these findings indicate that the joint disease of these mutant mice illustrated destruction of articular cartilage with features of chronic synovitis in various joints, including the major weight-bearing ones.
Molecular mechanism of joint disease in gp130ΔSTAT/ΔSTAT mice
Cartilage destruction associated with synovial hyperplasia is a major event in the early, effector phase of RA. Proinflammatory cytokines, including IL-6, are known to be involved in cartilage destruction in the disease. IL-6 is a potent mitogen for synovial fibroblasts in inflammatory joint diseases, including RA . Mutant synovial fibroblasts derived from the clinically unaffected knee joints exhibited high sensitivity and a proliferative response to IL-6 in comparison with those from control mice. This hyper-responsiveness of the mutant synovial cells to IL-6 is caused by sustained activation of the SHP-2/Ras/Erk pathway. Transcription of genes of the SOCS family, which are negative regulatory molecules, is activated by STAT-mediated signals. SOCS-1 in particular, which can be induced by various cytokines, such as IFN-γ, IL-4, IL-2, and IL-6, inhibits JAK-mediated cytokine signals by binding to JAKs [8, 9, 10]. In the mutant synovial cells, SOCS-1 mRNA induction by IL-6 treatment was markedly less than that in control cells. Moreover, synovial cells of IFN-γ-deficient SOCS-1-/- mice, which are rescued from the perinatal lethality usually associated with SOCS-1 deficiency , also displayed sustained SHP-2/Ras/Erk activation by IL-6 stimulation in comparison with control cells. In addition, the synovial cells derived from these doubly mutant mice showed high [3H]thymidine incorporation in response to IL-6. Collectively, these findings show that the hyper-responsiveness of gp130ΔSTAT/ΔSTAT synovial cells associated with the sustaining of SHP-2/Ras/Erk MAPK activation is due to a lack of SOCS-1 induction, caused by failure of STAT-mediated signals. That is, the disturbed balance between STAT and SHP-2 pathways can be attributed to hyper-responsiveness of synovial cells to IL-6, resulting in joint disease.
The study of gp130ΔSTAT/ΔSTAT mice reveals the following two points. First, consistent with previous reports, gp130-mediated STAT and SHP-2/Ras/Erk signal pathways play reciprocal roles in immune responses, permitting balanced activation of the two pathways [7, 13]. The in vivo findings have elucidated the direct involvement of sustained SHP-2/Ras/Erk MAPK activation in joint disease. Second, IL-6 plays a key role in the development of RA . The gp130ΔSTAT/ΔSTAT mouse, which we can accept as a model for spontaneously occurring RA, is a useful mouse model for the study of the molecular mechanism of RA and should provide new and important insights for an understanding of the molecular mechanisms in the pathogenesis of RA. However, no one yet knows whether endogenous IFN-γ mediated signals are involved in the joint disease of the gp130ΔSTAT/ΔSTAT mouse. Hyper-responsiveness of synovial cells from IFN-γ-deficient SOCS-1-/- mice was less marked than in those from gp130ΔSTAT/ΔSTAT mice. Furthermore, previous studies showed that these doubly mutant mice are free from any pathological changes [12, 14]. These results suggest that IFN-γ may play a role in development of RA in gp130ΔSTAT/ΔSTAT mice. It is worth mentioning that defective induction of SOCS-3 due to lack of STAT3 may contribute to the joint disease of the gp130ΔSTAT/ΔSTAT mouse: previous reports showed that SOCS-3 can strongly inhibit IL-6 signaling by competing for the SHP-2-gp130 interaction site by binding to the SH2-domain-containing SHP-2-interaction site in gp130 [15, 16]. IFN-γ-deficient gp130ΔSTAT/ΔSTAT mice and conditional SOCS-3-deficient mice will give us these answers.
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