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

Miyata M, Lee JY, Susuki-Miyata S, Wang WY, Xu H, Kai H, Kobayashi KS, Flavell RA, Li JD
Source: Nat Commun.
Publication Date: (2015)
Issue: 6: 6062
Research Area:
Basic Research
Cells used in publication:
Epithelial, bronchial (NHBE), human
Species: human
Tissue Origin: lung
Monocyte, human
Species: human
Tissue Origin: blood
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.