ReviewInhibition of IL-6 family cytokines by SOCS3
Section snippets
Introduction: IL-6 signalling
IL-6 is a pleiotropic cytokine that exerts both inflammatory and anti-inflammatory effects depending upon its cellular context and is an important differentiation factor during haematopoiesis (reviewed in [1]). IL-6 belongs to a family of cytokines that also include IL-11, IL-27, LIF, OSM, CT-1 and CNTF. These cytokines are structurally similar [2] and signal via association with cell-surface trans-membrane receptors that each consist of a dimer (or higher-order oligomer) of the common shared
Discovery of the SOCS proteins
In 1997 the SOCS family of proteins were discovered concurrently by the groups of Hilton (Walter and Eliza Hall Institute, Australia), Yoshimura (Kurume University, Japan) and Kishimoto (Osaka University, Japan) [16], [17], [18]. Each group used a different approach. Hilton et al., used an expression cloning methodology to identify proteins capable of inhibiting the IL-6-induced differentiation of the mouse M1 myelomonocytic cell-line and discovered, and named, SOCS1 (Suppressor of Cytokine
The SOCS family
Evolutionarily, SOCS proteins are first seen in animals having bilateral symmetry [23]. Recent analyses suggest the existence of three SOCS proteins in these organisms: orthologues of CIS/SOCS1/SOCS2/SOCS3 as well as SOCS4/5 and SOCS6/7 [23], [24]. Whilst certain species, most notably the fruit fly Drosophila melanogaster have lost one or more of these three subgroups, they are all represented in vertebrates where they have expanded to form the eight family members seen in mammals. Of these
SOCS3 is the primary regulator of IL-6 signalling
Despite SOCS1 being discovered on the basis of its ability to inhibit IL-6 action when overexpressed [17], [18], genetic deletion studies have surprisingly shown that SOCS1 plays little, if any, role in inhibiting IL-6 in vivo [43]. Rather it is SOCS3 that is the family member responsible for inhibiting IL-6 under physiological conditions [44], [45], [46]. This is a cautionary tale regarding the interpretation of the effects of individual SOCS proteins on various cytokines; whilst many SOCS
SOCS3 controls the duration of IL-6 signalling
Genetic deletion of SOCS3 in mice is lethal due to placental insufficiency as a result of dysregulated signalling by LIF [48]. Therefore, confirmation of the important role that SOCS3 plays in regulating signalling by other IL-6 family members, including IL-6 itself, has been via conditional knockout of the Socs3 gene. The first such studies were knockouts of SOCS3 in hepatocytes [46] and macrophages [44] (using cre recombinase under control of the Albumin or LysM promoters respectively) and
SOCS3 shapes the cell's response to IL-6
As well as controlling the duration of IL-6 signalling, SOCS3 also helps shape the cell's response to IL-6. For example, the transcriptional output of Socs3−/− macrophages stimulated with IL-6 differs not just quantitatively but also qualitatively from that of wild-type cells. In particular, loss of SOCS3 leads to an IL-6-induced transcriptional response that in part resembles that for interferon-γ with a number of interferon-inducible genes being switched on by IL-6 in these cells [51].
SOCS3 interacts with gp130, the shared receptor for IL-6 family cytokines
STAT3 is activated by a number of different cytokines and is a powerful inducer of SOCS3 expression [54]. However, SOCS3 only feeds back to inhibit STAT3 that is activated in response to particular cytokines (for example IL-6) and not others (for example IL-10 or interferon-γ) [44], [51], [55]. The key to this specificity is that SOCS3 directly interacts with gp130, the co-receptor for IL-6 family cytokines [56], [57], [58]. This allows SOCS3 to specifically target the IL-6 signalling cascade
The kinase inhibitory region (KIR) of SOCS3 allows it to directly inhibit JAK's catalytic activity
SOCS3 in mice and humans is a 225 amino acid protein that, like all SOCS proteins, contains an SH2 domain (residues 45–185) and a SOCS box domain (residues 186–225) [18], [22]. SOCS3 also contains a short N-terminal segment (residues 1–44), the most notable feature of which is the so-called Kinase Inhibitory Region (KIR) [77], [78], [79], [80], an 8–12 amino acid sequence that allows it to directly inhibit JAK's catalytic domain and is absolutely required for function (Fig. 2b).
The existence of
SOCS3 inhibits JAK1, JAK2 and TYK2 but not JAK3
Whilst the KIR is required to inhibit JAK, it is not sufficient. There is no detectable inhibition of JAK using a SOCS3 KIR peptide [82]. The structure of SOCS3 bound to JAK2 shows that only approximately 20% of the buried surface area within the complex involves the KIR. The majority of the SOCS3:JAK affinity is derived from an interaction between the SH2 domain of SOCS3 and JAK. It is important to note that this does not involve the classical phosphotyrosine binding groove on the SH2 domain,
A model of SOCS3 inhibition of IL-6 signalling
Knockout studies have shown that SOCS3 is a highly potent and specific inhibitor of IL-6 family cytokines, G-CSF and leptin, despite the fact that its expression is induced by a much larger number of cytokines. Any model of SOCS3 action must explain this specificity. Our model is centred upon the fact that SOCS3 binds JAK and the IL-6 receptor simultaneously via two opposing surfaces. Thus it is a particular JAK/receptor complex that is the true target of SOCS3, rather than an individual JAK or
Acknowledgments
The original research described in this review was supported by the National Health and Medical Research Council of Australia (programme grant nos. 461219 and 487922, 1011804), the U.S. National Institutes of Health (grant no. CA22556), the Victorian State Government Operational Infrastructure Support Grant, and the NHMRC Independent Research Institutes Infrastructure Support Scheme (361646). N.A.N. acknowledges fellowship support from the National Health and Medical Research Council, L.N.V.
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