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Nat Commun. 2015 Jan 14;6:6062. doi: 10.1038/ncomms7062.

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

Author information

1
Center for Inflammation, Immunity &Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia 30302, USA.
2
1] Center for Inflammation, Immunity &Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia 30302, USA [2] Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York 14642, USA.
3
Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
4
Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M Health Science Center, College Station, Texas 77843, USA.
5
Department of Immunobiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520, USA.

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.

PMID:
25585690
PMCID:
PMC4309435
DOI:
10.1038/ncomms7062
[Indexed for MEDLINE]
Free PMC Article

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