The Atypical Inhibitor of NF-?B, I?B?, Controls Macrophage Interleukin-10 Expression.

ABSTRACT: Macrophages constitute a first line of pathogen defense by triggering a number of inflammatory responses and the secretion of various pro-inflammatory cytokines. Recently, we and others found that I?B?, an atypical I?B family member and transcriptional coactivator of selected NF-?B target genes, is essential for macrophage expression of a subset of pro-inflammatory cytokines, such as IL-6, IL-12, and CCL2. Despite defective pro-inflammatory cytokine expression, however, I?B?-deficient mice develop symptoms of chronic inflammation. To elucidate this discrepancy, we analyzed a regulatory role of I?B? for the expression of anti-inflammatory cytokines and identified I?B? as an essential activator of IL-10 expression. LPS-challenged peritoneal and bone marrow-derived macrophages from I?B?-deficient mice revealed strongly decreased transcription and secretion of IL-10 compared with wild-type mice. Moreover, ectopic expression of I?B? was sufficient to stimulate Il10 transcription. On the molecular level, I?B? directly activated the Il10 promoter at a proximal ?B site and was required for the transcription-enhancing trimethylation of histone 3 at lysine 4. Together, our findings show for the first time the I?B?-dependent expression of an anti-inflammatory cytokine that is crucial in controlling immune responses.

SUBMITTER: Horber S 

PROVIDER: S-EPMC4933459 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature