Putting the brakes on arthritis: can suppressors of cytokine signaling (SOCS) suppress rheumatoid arthritis?

Abstract

During the immune response, as in a great symphony, timing is everything. Imagine the disastrous night of November 3, 1822, when Beethoven conducted a revival of his popular opera Fidelio. The musicians played their parts from the score perfectly but missed every cue of the great master, who was deaf to everything but his own imagination. The evening ended in chaos. The critical role for molecular cues firing at the right time is also true for the cellular players of the immune network, a system stitched together by the interplay of multiple cytokines. These peptide signals coordinate cell survival, migration, proliferation, and activation of cellular effector function. Not only do the right cytokine signals have to be initiated at the right time, but the duration of each signal must be perfectly controlled. Otherwise, disasters like autoimmunity or malignancies of the hematopoietic system can result. The longevity of cytokine signals transduced by the JAK/STAT pathway is regulated, in part, by a family of endogenous JAK kinase inhibitor proteins referred to as suppressors of cytokine signaling (SOCS) (1, 2). The SOCS family contains eight members of related proteins that share a common modular organization of an SH2 domain followed by a SOCS-box (reviewed in ref. 3). Two members of this family, SOCS-1 and SOCS-3, are potent inhibitors of JAK kinase family members. Both SOCS-1 and SOCS-3 bind to the positive regulatory tyrosine in the activation loop of JAK kinases through their respective SH2 domains, thereby occluding the accessibility of the active site to substrates (4). The tissue expression patterns of SOCS proteins are complex and distinct for each family member. Several SOCS members are early-response genes for a variety of cytokines and growth factors. For example, IL-6 induces SOCS-1, erythropoietin induces SOCS-2, and TNF-α induces SOCS-3, while IFN-γ potently induces all three family members. The transcriptional regulation of these SOCS family members appears to be under the exquisite control of the STAT transcription factors. Since SOCS-1 and SOCS-3 expression is tightly coupled to upstream cytokine signaling events it appears that they function as components of a negative feedback loop to dynamically terminate cytokine-mediated signals. Support for this model has been borne out by analysis of mice lacking SOCS proteins. SOCS-1–deficient mice die 3 weeks after birth as a result of unbridled IFN-γ signaling leading to widespread myelomonocytic infiltration of visceral organs and skin (5, 6). Socs1–/–/IFN-γ+/– mice develop an autoimmune polymyositis about 160 days after birth (7). Deficiency in SOCS-3 in mice results in embryonic lethality at day 12–16 and fetal liver erythrocytosis (8). For more on the central role of SOCS-3 in neuro-endocrine cross-regulation, see the Perspective by Auernhammer and Melmed in this issue (9).