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

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.

Cistrome-based Cooperation between Airway Epithelial Glucocorticoid Receptor and NF-κB Orchestrates Anti-inflammatory Effects

“…Furthermore, we identified inductive synergy between GR and NF-B at a novel enhancer within the TNFAIP3 locus and proposed a model in which cooperation between GR and NF-B at anti-inflammatory loci is central to the therapeutic effects of GCs. Subsequent studies by other researchers have supported this notion, with co-induction of IRAK3 (frequently referred to as IRAKM) and Sphk1 by GR and inflammatory stimuli linked to anti-inflammatory effects of GCs in various models of lung disease (37,38). Thus, cooperative gene induction mediated by convergence of activated GR and inflammatory signals at specific enhancers appears to contribute to the anti-inflammatory properties of GCs.…”

“…However, these prior studies did not specifically recognize cooperative regulation of anti-inflammatory targets by GR and p65 as a potential mechanism underlying the therapeutic effect of GCs. Instead, several studies, including our own publication on regulation of TNFAIP3 by GR and p65 and subsequent work by other groups on Sphk1 and IRAK3 (37,38), have established that this principal applies on a case-by-case basis to these individual genes. In the work presented here, we have extended these findings using genome-wide methodology to identify numerous additional genes that are regulated through this paradigm.…”

Glucocorticoid and TNF signaling converge at A20 (TNFAIP3) to repress airway smooth muscle cytokine expression

“…Although GR is widely understood to repress NF-B activity, we and others have collectively identified regulatory elements in which GR and p65 appear to cooperatively enhance transcription in several cell types (28,43,63). To test whether a similar mechanism operates in HASM, we transfected HASM2 and FA-HASM1 cells with a TNFAIP3 luciferase reporter (pTNFAIP3) that we have shown exhibits cooperative regulation by GR and NF-B in airway epithelial cells (1).…”

Genome Expression Profiling-Based Identification and Administration Efficacy of Host-Directed Antimicrobial Drugs against Respiratory Infection by Nontypeable Haemophilus influenzae

“…Chronic respiratory patients are prescribed anti-inflammatory therapies, which may influence NTHi infection. In fact, glucocorticoids modify NTHi gene expression (20), suppress host inflammation via the upregulation of IRAK-M, enhance NTHi-induced Tolllike receptor 2 (TLR2), and inhibit NTHi-induced MUC5A expression via mitogen-activated protein kinase (MAPK) phosphatase MKP-1-dependent inhibition of p38 MAPK (21)(22)(23)(24). Moreover, although glucocorticoids attenuate NTHi-triggered inflammation in vivo, they also compromise bacterial clearance (25).…”