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J Biol Chem. 2010 Jun 18;285(25):19593-604. doi: 10.1074/jbc.M109.069955. Epub 2010 Apr 13.

Inflammation anergy in human intestinal macrophages is due to Smad-induced IkappaBalpha expression and NF-kappaB inactivation.

Author information

  • 1Department of Medicine Gastroenterology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA. lesmy@uab.edu.

Abstract

Human intestinal macrophages contribute to tissue homeostasis in noninflamed mucosa through profound down-regulation of pro-inflammatory cytokine release. Here, we show that this down-regulation extends to Toll-like receptor (TLR)-induced cytokine release, as intestinal macrophages expressed TLR3-TLR9 but did not release cytokines in response to TLR-specific ligands. Likely contributing to this unique functional profile, intestinal macrophages expressed markedly down-regulated adapter proteins MyD88 and Toll interleukin receptor 1 domain-containing adapter-inducing interferon beta, which together mediate all TLR MyD88-dependent and -independent NF-kappaB signaling, did not phosphorylate NF-kappaB p65 or Smad-induced IkappaBalpha, and did not translocate NF-kappaB into the nucleus. Importantly, transforming growth factor-beta released from intestinal extracellular matrix (stroma) induced identical down-regulation in the NF-kappaB signaling and function of blood monocytes, the exclusive source of intestinal macrophages. Our findings implicate stromal transforming growth factor-beta-induced dysregulation of NF-kappaB proteins and Smad signaling in the differentiation of pro-inflammatory blood monocytes into noninflammatory intestinal macrophages.

PMID:
20388715
[PubMed - indexed for MEDLINE]
PMCID:
PMC2885238
Free PMC Article

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