gp130 at the nexus of inflammation, autoimmunity, and cancer

Abstract

Glycoprotein 130 (gp130) is a shared receptor utilized by several related cytokines, including IL-6, IL-11, IL-27, Leukemia Inhibitory Factor (LIF), Oncostatin M (OSM), Ciliary Neurotrophic Factor (CNTF), Cardiotrophin 1 (CT-1) and Cardiotrophin-like Cytokine (CLC). Gp130 plays critical roles during development and gp130-deficient mice are embryonically lethal. However, the best characterized facet of this receptor and its associated cytokines is the ability to promote or suppress inflammation. The aim of this review is to discuss the role of gp130 in promoting or preventing the development of autoimmunity and cancer, two processes that are associated with aberrant inflammatory responses.

Figure 1.. gp130-mediated signaling.

(A) gp130 family cytokines, in this case, IL-6, bind their specific receptor α chains, which triggers association with gp130 and formation of a multimeric complex. (B) Receptor-associated JAK molecules are phosphorylated and in turn, phosphorylate and activate recruited STAT molecules (pSTAT). gp130 signaling typically activates STAT1, -3, and/or -5. As a consequence of receptor engagement, SHP2 is recruited and can activate the PI3K or ERK/MAPK pathways downstream, although relatively little is understood about the biological significance of these pathways. (C) SOCS3 is up-regulated in response to STAT1 and STAT3 and can bind directly to gp130 and block signal transduction, thus acting in a negative-feedback loop.

Figure 2.. SOCS3 regulates the quality of gp130-mediated signaling.

(A) In WT cells, IL-6 signaling results in an abbreviated period of STAT3 activation. (B) This contrasts with IL-10 signaling, which also uses STAT3, but results in a more sustained period of STAT3 activation. (C) In gp130 Y757F or Y759F mice or in mice that genetically lack SOCS3, IL-6-mediated activation of STAT3 is more sustained. In this case, IL-6 acquires the ability to block proinflammatory cytokine production from activated macrophages. These studies demonstrate that SOCS3 regulates the nature of the cellular response to gp130-mediated signals. Although STAT signaling is sustained in the absence of SOCS3, other unclear mechanisms can compensate, and the signal terminates eventually.

Figure 3.. gp130 family cytokines are highly pleiotropic.

Despite the shared use of a receptor, gp130 family cytokines have several overlapping and opposing functions. IL-6, IL-11, and OSM (A–C) can promote fibrosis and osteoclastogenesis, and IL-27 blocks the differentiation of osteoclasts (D). Alternatively, IL-6 and IL-11 have been linked to proliferation of cancer cells, and OSM and IL-27 block proliferation of these cells. In the context of autoimmunity, IL-6 is a critical differentiation factor for Th17 cells and can promote Th2 differentiation, and IL-27 is a prominent inhibitor of multiple T cell subsets. Despite this anti-inflammatory ability, IL-27 can promote antitumor immunity in several cancer models (D). Understanding the factors regulating context-dependent harmful versus beneficial outcomes of gp130-mediated signaling is important, considering the interest in manipulation of these pathways therapeutically.