SOCS as Immune Modulator

Abstract

Suppressor of cytokine signaling (SOCS) proteins inhibit signaling through cytokine receptors by inhibiting Janus protein kinases (JAKs) and thus blocking activation of STAT (signal transducers and activators of transcription) transcription factors. Although experiments with overexpression of the SOCS3 molecule have indicated that it might suppress signaling by several cytokines, three new papers on the effects of tissue-specific loss of SOCS3 function in vivo in macrophages show that physiological regulation by SOCS3 is focused on regulation of signaling by interleukin 6 (IL-6) and the gp130 receptor subunit. Furthermore, the results presented show that loss of SOCS3 not only modulates the strength of IL-6 signals (which are normally inflammatory), but also causes qualitative changes in the signal such that the spectrum of gene expression induced by IL-6 is shifted and resembles more closely an immunosuppressive response to interferons. The new results help explain how similar signaling mechanisms can be coupled to distinct, even opposing, functional outputs. IL-6 and IL-10 normally have pro- and anti-inflammatory actions, respectively, even though they both activate STAT3. But in macrophages lacking SOCS3, IL-6 produces a more prolonged activation of STAT3, similar to that produced by IL-10, and also produces an anti-inflammatory biological response. Thus, SOCS3 seems to be necessary to prevent anti-inflammatory signaling by IL-6. Because IL-6 is implicated in diseases associated with excessive inflammation, like arthritis, inhibition of SOCS3 activity in macrophages could be used to therapeutic effect. The three papers are discussed in context by Johnston and O'Shea.H. Yasukawa, M. Ohishi, H. Mori, M. Murakami, T. Chinen, D. Aki, T. Hanada, K. Takeda, S. Akira, M. Hoshijima, T. Hirano, K. R. Chien, A. Yoshimura, IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Nat. Immunology 4, 551-556 (2003). [Online Journal]R. Lang, A. -L. Pauleau, E. Parganas, Y. Takahashi, J. Mages, J. N. Ihle, R. Rutschman, P. J. Murray, SOCS3 regulates the plasticity of gp130 signaling. Nat. Immunology 4, 546-550 (2003). [Online Journal]B. A. Croker, D. L. Krebs, J. -G. Zhang, S. Wormald, T. A. Willson, E. G. Stanley, L. Robb, C. J. Greenhalgh, I. Förster, B. E. Clausen, N. A. Nicola, D. Metcalf, D. J. Hilton, A. W. Roberts, W. S. Alexander, SOCS3 negatively regulates IL-6 signaling in vivo. Nat. Immunology 4, 540-545 (2003). [Online Journal]J. A. Johnston, J. J. O'Shea, Matching SOCS with function. Nat. Immunology 4, 507-509 (2003). [Online Journal]