Mitochondrial respiratory complex III sustains IL-10 production in activated macrophages and promotes tumor-mediated immune evasion
Alessia Zotta, Juliana E. Toller-Kawahisa, Eva M. Pålsson‐McDermott, Shane M. O’Carroll, Órlaith C. Henry, Emily A. Day, Anne F. McGettrick, Ross W. Ward, Dylan G. Ryan, Mark A. Watson, Martin D. Brand, Marah C. Runtsch, Kathrin Maitz, Anna Lueger, Julia Kargl, Jan Lj. Miljković, Ed C. Lavelle, Luke O'neill
Abstract
The cytokine interleukin-10 (IL-10) limits the immune response and promotes resolution of acute inflammation. Because of its immunosuppressive effects, IL-10 up-regulation is a common feature of tumor progression and metastasis. Recently, IL-10 regulation has been shown to depend on mitochondria and redox-sensitive signals. We have found that Suppressor of site III Qo Electron Leak 1.2 (S3QEL 1.2), a specific inhibitor of reactive oxygen species (ROS) production from mitochondrial complex III, and myxothiazol, a complex III inhibitor, decrease IL-10 in lipopolysaccharide (LPS)–activated macrophages. IL-10 down-regulation is likely to be mediated by suppression of c-Fos, which is a subunit of activator protein 1 (AP1), a transcription factor required for IL-10 gene expression. S3QEL 1.2 impairs IL-10 production in vivo after LPS challenge and promotes the survival of mice bearing B16F10 melanoma by lowering tumor growth. Our data identify a link between complex III–dependent ROS generation and IL-10 production in macrophages, the targeting of which could have potential in boosting antitumor immunity.