IL-1 Family Members in Cancer; Two Sides to Every Story

Abstract

The IL-1 family of cytokines currently comprises of seven ligands with pro-inflammatory activity (IL-1α and IL-1β, IL-18, IL-33, IL-36α, IL-36β, IL-36γ) as well as two ligands with anti-inflammatory activity (IL-37, IL-38). These cytokines are known to play a key role in modulating both the innate and adaptive immunes response, with dysregulation linked to a variety of autoimmune and inflammatory diseases. Given the increasing appreciation of the link between inflammation and cancer, the role of several members of this family in the pathogenesis of cancer has been extensively investigated. In this review, we highlight both the pro- and anti-tumorigenic effects identified for almost all members of this family, and explore potential underlying mechanisms accounting for these divergent effects. Such dual functions need to be carefully assessed when developing therapeutic intervention strategies targeting these cytokines in cancer.

Keywords: IL-18; IL-33; IL-36 family interleukins; cancer; inflammation; interleukin-1 (IL-1).

Figure 1

Functions of IL-1β signaling in cancer. The IL-1 signaling pathway is activated through the binding of IL-1α or IL-1β to the IL-1RI. This is followed by dimerization of IL-1R1 with IL-1RAcP. This interaction may be competitively inhibited by the IL-1RA and IL-38. Agonist binding is followed by engagement of further signaling intermediates with subsequent activation of transcription factors such as NF-κB and AP-1. Transcription of inflammatory genes is upregulated which may then result in pro-tumorigenic or anti-tumorigenic phenotypes.

Figure 2

IL-36 Signaling in cancer. IL-36 signaling is achieved through binding of the IL-36α, IL-36β or IL-36γ cytokines to the IL-36 Receptor (IL1RL2), along with the transmembrane accessory protein, IL-1RAcP. This binding may be inhibited through competitive binding of IL-36RA or IL-38. Agonist binding is followed by subsequent engagement and phosphorylation of intracellular signaling molecules to activate transcription factors such as NF-κB and AP-1. This promotes the observed anti-tumorigenic phenotype, which may be achieved by increased IFN-γ production, reduced immunosuppression and increased immune cell recruitment to the local tumor microenvironment.