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

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 glucocorticoid...

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Bibliographic Details
Published in:	Nature communications 2015-01, Vol.6 (1), p.6062-6062, Article 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:	Article
Language:	eng
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
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Summary:	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.
ISSN:	2041-1723 2041-1723