The central role of SOCS-3 in integrating the neuro-immunoendocrine interface

Neuro-immune interfaceCytokines and related signaling molecules lead to profound regulatory changes in differentiated cell function, modulating immune functions, the stress response, energy metabolism, growth, and reproduction.A network of intracellular molecules that dampen or inhibit the effects of these pleiotropic factors provides a crucial counterbalance to cytokine signals.Recent studies have shown that negative feedback, initiated in the various target tissues by the cytokines themselves, is central to endocrine homeostasis.Cytokine-mediated adrenocorticotropin hormone (ACTH) and cortisol overproduction, for instance, is prevented by tightly regulated cytokine-induced intracellular negative control systems.Likewise, growth hormone (GH) signaling is abrogated by cytokine-induced proteins, providing an explanation for GH resistance and stunted growth observed in states of elevated cytokine activity, including inflammation, starvation, and chronic illness.This article explores the role of the signal suppressor SOCS-3 in inhibiting the actions of neuro-endocrine cytokines and hormones, while maintaining the plasticity of the ultimate neuroimmune endocrine responses. SOCS proteins as inhibitors of the JAK-STAT cascadeThe JAK-STAT cascade is an intracellular signaling pathway shared by a variety of cytokines, including gp130 cytokines (IL-6, IL-11, leukemia inhibitory factor), as well as leptin, GH, and prolactin.Ligand binding to cytokine receptors, which themselves lack intrinsic kinase activity, activates receptor-associated Janus kinases (JAK's) by autophosphorylation and subsequent tyrosine phosphorylation of the receptor's cytoplasmic domain and of associated proteins termed STATs for signal transducers and activators of transcription.Tyrosine phosphorylation of STATs enables homo-or heterodimerization of various STAT proteins.The dimerized STAT complexes translocate to the nucleus, where they transactivate their target genes by binding to specific promoter elements (1, 2).A family of proteins able to inhibit the JAK-STAT signaling cascade has synonymously been described as suppressor of cytokine signaling (SOCS) protein (3), JAK-binding protein (4), and STAT-induced STAT inhibitor.The SOCS protein family (5) encompasses SOCS-1 (3, 4, 6), SOCS-2 (3), SOCS-3 (3), CIS (7), and SOCS-4 to SOCS-7 (5).While the role of the former four proteins is increasingly well understood, the roles of SOCS-4 to SOCS-7 remain poorly characterized.In vitro overexpression studies demonstrate that SOCS-1 and SOCS-3 exert similar effects and represent the most potent and broadly acting suppressors of cytokine signaling.These factors potently inhibit JAK-STAT signaling of several gp130 cytokines (see Arzt, this Perspective series, ref. 8; and refs.3,4,[9][10][11][12], GH (13-15), and prolactin (16).The common protein structure of SOCS proteins is a variable N-terminal region, a central SH2 domain, and a C-terminal domain, termed SOCS-box motif (5).The central SH2 domain alone is not sufficient for inhibiting JAK-STAT signaling (4), as part of the N-terminal region, termed pre-SH2 domain/kinase inhibitory region, is also required (10,17,18).The C-terminal SOCS-box interacts with elongin BC complex (19), although the physiological significance of this interaction is still unclear.Some observations suggest that this interaction protects SOCS proteins from degradation in the ubiquitin-proteasome pathway, whereas others suggest that it actually directs these proteins to the ubiquitin-proteasome pathway and sets the stage for their degradation (19,20).Conversely, the significance of the proteasome in the turnover of these molecules is not in doubt.The halflives of SOCS-1 and SOCS-3 in COS-7 cells have been calculated to be as short as 1.5 hours ( 21), but incubation with proteasome inhibitors stabilizes them significantly (18,19).Therefore, the C-terminal SOCS-box also appears not to be essential for direct inhibitory interaction with JAK (10, 17) but might be required to control SOCS protein degradation and thus might modulate the intracellular level of the SOCS protein (18).