SOCS1 and SOCS3 in the control of CNS immunity

Abstract

In the decade following their initial discovery, the suppressor of cytokine signaling (SOCS) proteins have been studied for their potential use as immunomodulators in disease. SOCS proteins, especially SOCS1 and SOCS3, are expressed by immune cells and cells of the central nervous system (CNS) and have the potential to impact immune processes within the CNS, including inflammatory cytokine and chemokine production, activation of microglia, macrophages and astrocytes, immune cell infiltration and autoimmunity. We describe CNS-relevant in vitro and in vivo studies that have examined the function of SOCS1 or SOCS3 under various neuroinflammatory or neuropathological conditions, including exposure of CNS cells to inflammatory cytokines or bacterial infection, demyelinating insults, stroke, spinal cord injury, multiple sclerosis and glioblastoma multiforme. The SOCS familySuppressor of cytokine signaling (SOCS) proteins are intracellular, cytokine-inducible proteins that inhibit cytokine signaling in numerous cell types, including cells of the immune and central nervous systems (CNS). The SOCS family is composed of eight members: cytokine inducible SRC homology 2 (SH2)-domain-containing protein (CIS) and SOCS1 to SOCS7 [1,2]. To exert their function, SOCS proteins associate with phosphorylated tyrosine residues on Janus kinases (JAKs) and/or cytokine receptor subunits through a central SH2 domain. A C-terminal SOCS box then interacts with components of the ubiquitin ligase machinery and mediates proteosomal degradation of associated proteins [3]. In addition, the N-terminus of SOCS1 and SOCS3, specifically, contains a kinase-inhibitory region (KIR) (Figure 1), which acts as a pseudosubstrate for JAKs, conferring inhibition of JAK kinase activity [1]. Through these interactions, SOCS proteins attenuate responses to cytokines and growth factors. Because studies of SOCS family members have established SOCS1 and SOCS3 as the most important in regulating innate and adaptive immune responses, they are the focus of this review. There is limited information regarding the role of other SOCS family members in CNS immunity. Therefore, they are not discussed here. SOCS regulation of JAK/STAT signalingSignal transduction through the JAK/signal transducer and activator of transcription (STAT) signaling pathway is a crucial mediator of inflammatory and immune responses in the CNS [4]. Activation of the JAK/STAT pathway is achieved by cytokines binding to their associated cell-surface receptors, leading to a series of phosphorylation events, culminating in phosphorylation of the STAT transcription factors (Figure 2). Activated STATs promote Corresponding author: Benveniste, E.N. (tika@uab.edu). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Plea...

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