Abstract
Immune and inflammatory systems are controlled by multiple cytokines, including interleukins (ILs) and interferons. These cytokines exert their biological functions through Janus tyrosine kinases and STAT transcription factors. We recently identified suppressors of cytokine signaling (SaCS) family genes which inhibit JAK tyrosine kinase activity and cytokine signal transduction. Among them, SaCS3 playa negative regulatory role in the IL-6/ gp130 signaling pathway. We showed the activation of STAT3 and induction of SaCS3 in chronic inflammation, including rheumatoid arthritis (RA) and inflammatory bowel diseases (IBD). To define the physiological role of SaCS3 induction in colitis, we developed a sacs1 mutant (F59DJAB) that overcame the inhibitory effect of both sacs1 and SacS3 and created transgenic mice. Stronger STAT3 activation and more severe colitis developed in F59D-JAB-transgenic mice than in their wild-type littermates. Next, the importance of STAT3 activation and SaCS3 induction in RA was examined by adenoviral transfer to overexpress SaCS3 or a dominant negative form of STAT3 (dnSTAT3) in synoviocytes isolated from patients with RA. The proliferation of cells infected with either of these constructs was significantly reduced, as was the production of IL-6. These results show that the proliferation and cytokine production of RA-synoviocytes in vitro is dependent on JAK/STAT3 signaling, and that these processes can be inhibited by the expression of SacS3 or dnSTAT3. We then injected SaCS3 and dnSTAT3 adenovirus into the ankle joints of mice prone to antigen-induced arthritis (AlA) or collagen-induced arthritis (CIA). In these models, SOCS3 adenovirus prominently reduced the severity of arthritis and joint swelling compared with control animals. These data suggest that the hyperactivation of STAT3 results in severe colitis and arthritis, and that SOCS3 plays a negative regulatory role in inflammation by down-regulating the activity of STAT3. Our study also suggests that adenovirus-mediated gene transfer of the SOCS3 gene could represent a new approach to effectively block the pathogenesis of RA.
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Yasukawa, H., Kinjyo, I., Yoshimura, A. (2003). Negative Regulator of Cytokine Signaling (SOCS) Genes in Inflammation. In: Matsumori, A. (eds) Cardiomyopathies and Heart Failure. Developments in Cardiovascular Medicine, vol 248. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-9264-2_3
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DOI: https://doi.org/10.1007/978-1-4419-9264-2_3
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