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

• Published in: Nature communications Vol. 6; no. 1; p. 6062
• Main Authors: Miyata, Masanori, Lee, Ji-Yun, Susuki-Miyata, Seiko, Wang, Wenzhuo Y, Xu, Haidong, Kai, Hirofumi, Kobayashi, Koichi S, Flavell, Richard A, Li, Jian-Dong
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 14.01.2015; Nature Pub. Group
• Subjects: Animals; Blotting, Western; Cell Line; Chromatin Immunoprecipitation; Glucocorticoids - therapeutic use; Haemophilus influenzae - immunology; Haemophilus influenzae - pathogenicity; Humans; Inflammation - drug therapy; Inflammation - metabolism; Interleukin-1 Receptor-Associated Kinases - genetics; Interleukin-1 Receptor-Associated Kinases - metabolism; Male; Mice; Mice, Inbred C57BL; Reverse Transcriptase Polymerase Chain Reaction; Up-Regulation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms7062

Glucocorticoids 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.