IRAK-M is a negative regulator of Toll-like receptor signaling.

By Koichi S. Kobayashi, L. Hernandez, J. Galán, C. Janeway, R. Medzhitov, R. Flavell. Cell, 2002

1,241 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Immunology

View Paper: https://www.semanticscholar.org/paper/d207b2bad0a8a2855409cf575129ccb2eab1e7d8

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Citations in the corpus

• Function of Nod‐like receptors in microbial recognition and host defense (2009, background): “Lara-Tejero M, et al. Role of the caspase- 1 inflammasome in Salmonella typhimurium pathogenesis.”
• Pathogen Recognition and Inflammatory Signaling in Innate Immune Defenses (2009, background): “Importantly, IRAK-M-deficient mice secrete elevated levels of proinflammatory cytokines and are defective in induction of LPS tolerance (191).”
• Hyaluronan as an Immune Regulator in Human Diseases (2011, positive): “We further found that the induction of the negative regulators of TLR signaling IL-1Rassociated kinase-M (215), Toll-interacting protein, and A20 by intratracheal lipopolysaccharide (LPS) in vivo and in macrophages in vitro was significantly reduced in CD44 / mice, suggesting that CD44 plays a role ”
• Molecular Mechanisms That Influence the Macrophage M1–M2 Polarization Balance (2014, background): “Along the same lines, chronic signaling through the TLR4 pathway has been shown to induce various negative regulators like IRAK-M, ST2, SOCS1, short version of MyD88 (MyD88sh) (27, 28) and SHIPs (29).”
• Akt1 controls macrophage response to LPS by regulating microRNAs (2009, background): “Mutations that interfere with these negative regulatory loops 220 Immunity 31, 220–231, August 21, 2009 ª2009 Elsevier Inc. promote hyperresponsiveness to LPS and inhibit the development of endotoxin tolerance (Kinjyo et al., 2002; Nakagawa et al., 2002; Kobayashi et al., 2002).”