Mitochondrial respiratory complex III sustains IL-10 production in activated macrophages and promotes tumor-mediated immune evasion

The cytokine interleukin (IL)-10 limits the immune response and promotes resolution of acute and chronic inflammation. Because of its immunosuppressive effects, IL-10 upregulation is a common feature of tumor progression and metastasis. Most recently, IL-10 regulation has been shown to depend on mitochondria and redox-sensitive signals. We have found that Suppressor of site IIIQo Electron Leak (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 production from Lipopolysaccharide (LPS) activated macrophages. IL-10 downregulation is likely to be mediated by the suppression of c-Fos, which is a subunit of Activator Protein (AP)-1, 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 specific targeting of which could have potential in the effort to boost anti-tumor immunity.

Methods
This dataset was collected after performing experiments on primary cultures of murine bone marrow-derived macrophages (BMDMs), murine B16F10 melanoma cells, human macrophages differentiated from peripheral blood mononuclear cells (PBMCs) and from in vivo experiments on mice.