[HTML][HTML] IRAK-M is a negative regulator of Toll-like receptor signaling

K Kobayashi, LD Hernandez, JE Galán, CA Janeway… - Cell, 2002 - cell.com
K Kobayashi, LD Hernandez, JE Galán, CA Janeway, R Medzhitov, RA Flavell
Cell, 2002cell.com
Toll-like receptors (TLRs) detect microorganisms and protect multicellular organisms from
infection. TLRs transduce their signals through MyD88 and the serine/threonine kinase
IRAK. The IRAK family consists of two active kinases, IRAK and IRAK-4, and two inactive
kinases, IRAK-2 and IRAK-M. IRAK-M expression is restricted to monocytes/macrophages,
whereas other IRAKs are ubiquitous. We show here that IRAK-M is induced upon TLR
stimulation and negatively regulates TLR signaling. IRAK-M prevented dissociation of IRAK …
Abstract
Toll-like receptors (TLRs) detect microorganisms and protect multicellular organisms from infection. TLRs transduce their signals through MyD88 and the serine/threonine kinase IRAK. The IRAK family consists of two active kinases, IRAK and IRAK-4, and two inactive kinases, IRAK-2 and IRAK-M. IRAK-M expression is restricted to monocytes/macrophages, whereas other IRAKs are ubiquitous. We show here that IRAK-M is induced upon TLR stimulation and negatively regulates TLR signaling. IRAK-M prevented dissociation of IRAK and IRAK-4 from MyD88 and formation of IRAK-TRAF6 complexes. IRAK-M−/− cells exhibited increased cytokine production upon TLR/IL-1 stimulation and bacterial challenge, and IRAK-M−/− mice showed increased inflammatory responses to bacterial infection. Endotoxin tolerance, a protection mechanism against endotoxin shock, was significantly reduced in IRAK-M−/− cells. Thus, IRAK-M regulates TLR signaling and innate immune homeostasis.
cell.com