Interleukin-1 Beta-A Friend or Foe in Malignancies?

Abstract

Interleukin-1 beta (IL-1β) is induced by inflammatory signals in a broad number of immune cell types. IL-1β (and IL-18) are the only cytokines which are processed by caspase-1 after inflammasome-mediated activation. This review aims to summarize current knowledge about parameters of regulation of IL-1β expression and its multi-facetted role in pathophysiological conditions. IL-1 signaling activates innate immune cells including antigen presenting cells, and drives polarization of CD4+ T cells towards T helper type (Th) 1 and Th17 cells. Therefore, IL-1β has been attributed a largely beneficial role in resolving acute inflammations, and by initiating adaptive anti-tumor responses. However, IL-1β generated in the course of chronic inflammation supports tumor development. Furthermore, IL-1β generated within the tumor microenvironment predominantly by tumor-infiltrating macrophages promotes tumor growth and metastasis via different mechanisms. These include the expression of IL-1 targets which promote neoangiogenesis and of soluble mediators in cancer-associated fibroblasts that evoke antiapoptotic signaling in tumor cells. Moreover, IL-1 promotes the propagation of myeloid-derived suppressor cells. Using genetic mouse models as well as agents for pharmacological inhibition of IL-1 signaling therapeutically applied for treatment of IL-1 associated autoimmune diseases indicate that IL-1β is a driver of tumor induction and development.

Keywords: inflammasome; interleukin-1β; myeloid-derived suppressor cell; promoter; tumor; tumor-associated macrophage.

Figure 1

IL-1β expression. Transcriptional and posttranscriptional regulation results in expression of functionally inactive pro-IL-1β. Stimulatory (green) and inhibitory (red) activities exerted by stimuli, signaling adaptors and TF are indicated by arrows. TF binding sites (boxes) within the IL-1β gene promoter that induce (green) or inhibit (orange) gene expression are named. The transcription start site is drawn (black arrow). Exons (boxes) encompass non-coding (yellow) and protein-coding (orange) regions. The derived IL-1β mRNA, and the location of the AU-rich elements (ARE) engaged by RNA-binding proteins are depicted. Pro-IL-1β is cleaved by active inflammasomes which yields bioactive IL-1 β.

Figure 2

IL-1 signaling in target cells. Binding of IL-1 to IL1R1/3 results in cellular activation due to stimulation of IKK and MKK. IL-1 signaling is blunted in case of binding of IL-1 to the decoy receptor IL1R2/3, and by competitive binding of IL-1Ra to IL1R1/3.

Figure 3

Effects of IL-1 in the tumor microenvironment. IL-1 is expressed by tumor cells, and predominantly by regulatory immune cell populations such as TAM and MDSC in the tumor microenvironment. The interleukin exerts pro-tumorigenic autocrine and paracrine effects on several levels in these cell types as well as in CAF which themselves do not generate IL-1 (blue arrows). Protumorigenic effects of elevated IL-1 on these different cell types are counter-acted by administration of IL-1Ra which competes with IL-1(α and β), and thereby prevents IL-1 signaling (red arrows). In numerous studies, TAM and MDSC were demonstrated to specifically produce IL-1β. In accordance, application of IL-1β specific antibodies intended to prevent induction of IL-1 signaling was shown to confer anti-tumorigenic effects as well.

Figure 4

Effects of BRAF inhibitors on IL-1β production by DC. Murine bone marrow-derived DC at (A) unstimulated state or (B) treated with LPS [100 ng/mL] were (co)administered with varying doses of BRAF inhibitors. DAB, but not ENC induced IL-1β production in DC at either state of activation (mean ± SD; n = 4).