The interleukin-1 receptor-associated kinase M selectively inhibits the alternative, instead of the classical NFkappaB pathway

J Innate Immun. 2009;1(2):164-74. doi: 10.1159/000158541.

Abstract

The innate immunity signaling process is controlled by numerous positive and negative regulators. The interleukin-1 receptor-associated kinase M (IRAK-M) is one of the negative regulators that contribute to the attenuation of NFkappaB activation. The molecular mechanism involved, however, is poorly defined. In this report, we observed that IRAK-M selectively suppresses the NIK-IKKalpha-mediated alternative NFkappaB pathway. Deletion of IRAK-M led to NIK stabilization, favored the formation of the IKKalpha/IKKalpha homodimer instead of the IKKalpha/IKKbeta heterodimer, and enhanced RelB nuclear distribution. In contrast, p65 nuclear localization and phosphorylation was not affected by IRAK-M deficiency. IRAK-M-deficient cells exhibited increased expression of selected cytokines such as IL-6 and GM-CSF, as well as quickened resynthesis of IkappaBalpha. The increased expression of IL-6 and GM-CSF was ablated when RelB expression was knocked down using specific siRNA. We also demonstrated that the observed inhibitory effect of IRAK-M was primarily limited to the TLR2 ligand, instead of TLR4. Taken together, our findings suggest that IRAK-M negatively regulates the alternative NFkappaB pathway in a ligand-specific manner.

Keywords: Alternative pathway; Computational simulation; IRAK-M; Innate immunity; NFκB; Signaling.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cells, Cultured
  • Down-Regulation
  • I-kappa B Kinase / metabolism
  • Immunity, Innate / physiology*
  • Interleukin-1 Receptor-Associated Kinases / metabolism*
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • Signal Transduction / immunology
  • Toll-Like Receptor 2 / metabolism

Substances

  • NF-kappa B
  • Tlr2 protein, mouse
  • Toll-Like Receptor 2
  • Interleukin-1 Receptor-Associated Kinases
  • Irak3 protein, mouse
  • I-kappa B Kinase