Glucocorticoids suppress inflammation via the upregulation of negative regulator IRAK-M.
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| Abstract |
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.
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| 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 |
| Journal | Nature communications (Nat Commun) Vol. 6 Pg. 6062 (Jan 14 2015) ISSN: 2041-1723 [Electronic] England |
| PMID | 25585690 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't) |
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