Glucocorticoids suppress inflammation via the upregulation of negative regulator IRAK-M

• DOI: 10.1038/ncomms7062
• Publication Date: 2015-01-14T09:59:57Z
• Authors: Masanori Miyata; Ji-Yun Lee; Seiko Susuki-Miyata; Wenzhuo Y. Wang; Haidong Xu; Hirofumi Kai; Koichi S. Kobayashi; Richard A. Flavell; Jian-Dong Li
• Keywords: Inflammation; Male; 0301 basic medicine; Chromatin Immunoprecipitation; Reverse Transcriptase Polymerase Chain Reaction; Blotting, Western; Haemophilus influenzae; Article; Cell Line; Up-Regulation; 3. Good health; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Interleukin-1 Receptor-Associated Kinases; Animals; Humans; Glucocorticoids

AbstractGlucocorticoids are among the most commonly used anti-inflammatory agents. Despite the enormous efforts in elucidating the glucocorticoid-mediated anti-inflammatory actions, how glucocorticoids tightly control overactive inflammatory response is not fully understood. Here we show that glucocorticoids suppress bacteria-induced inflammation by enhancing IRAK-M, a central negative regulator of Toll-like receptor signalling. The ability of glucocorticoids to suppress pulmonary inflammation induced by non-typeable Haemophilus influenzae is significantly attenuated in IRAK-M-deficient mice. Glucocorticoids improve the survival rate after a lethal non-typeable Haemophilus influenzae infection in wild-type mice, but not in IRAK-M-deficient mice. Moreover, we show that glucocorticoids and non-typeable Haemophilus influenzae synergistically upregulate IRAK-M expression via mutually and synergistically enhancing p65 and glucocorticoid receptor binding to the IRAK-M promoter. Together, our studies unveil a mechanism by which glucocorticoids tightly control the inflammatory response and host defense via the induction of IRAK-M and may lead to further development of anti-inflammatory therapeutic strategies.