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The effect of Interleukin-10 on macrophage activation and prostate cancer cell phenotype

University of British Columbia

Interleukin-10 (IL10) is best studied for its anti-inflammatory action on immune cells including macrophages, but it also exerts littler known effects on non-immune cells such as prostate cancer (PCa) epithelial cells. In this thesis I examined the contribution of an IL10-induced protein called EP4 on IL10 inhibition of macrophage activation, as well as the ability of IL10 to stimulate expression of proteins in PCa cells which are associated with tumour progression. Macrophages sense molecules on pathogens such as lipopolysaccharide (LPS) and respond by producing inflammatory cytokines including TNFα and other mediators which coordinate the host defense against the pathogen. IL10 is produced as part of the resolution (anti-inflammatory) phase of inflammation. IL10 receptor (IL10R) signalling in macrophages involves the STAT3 transcription factor and the SHIP1 inositol phosphatase which work together to support the expression of genes involved in the anti-inflammatory response. I report here that IL10 upregulates the expression of prostaglandin E2 (PGE2) receptor EP4. The EP4 receptor has previously been shown to mediate PGE2’s anti-inflammatory action. Knockdown of EP4 impaired IL10’s ability to inhibit LPS-induced signalling events and TNFα production. I propose that part of the IL10 anti-inflammatory effect on macrophages may thus be mediated through LPS-induced, autocrine PGE2, binding to IL10-induced EP4. The direct effect of IL10 on epithelial cancer cells has not been well studied. Serum levels of IL10 increase in PCa patients as their tumours progress, and this is thought to contribute to the suppressed immune system observed in these patients. PCa patients are treated with androgen antagonists such as enzalutamide (ENZ) to inhibit androgen receptor dependent PCa cell growth. Development of ENZ resistance is associated with tumour differentiation to a more aggressive neuroendocrine phenotype. I found that IL10 like ENZ, induce markers of neuroendocrine differentiation and inhibit androgen receptor reporter activity in PCa cells. Both also upregulated the levels of PDL1 (CD274) which would promote tumour survival in vivo through its interaction with the immune cell inhibitory receptor PD1 to suppress an anti-tumour immunity. These findings suggest that IL10’s direct action on PCa cells contributes to PCa progression independent of IL10’s suppression of host immune cells.

Text

2020-08-10

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/75412

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/