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

Academic Article

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.
  • Published In

    Keywords

  • Cytokines, Enzyme Inhibitors, Gene Expression Regulation, Enzymologic, Humans, I-kappa B Proteins, Inflammation, Intestinal Mucosa, Macrophages, Monocytes, NF-KappaB Inhibitor alpha, NF-kappa B, Oligonucleotide Array Sequence Analysis, Phosphorylation, Signal Transduction, Smad Proteins, Transforming Growth Factor beta
  • Digital Object Identifier (doi)

    Author List

  • Smythies LE; Shen R; Bimczok D; Novak L; Clements RH; Eckhoff DE; Bouchard P; George MD; Hu WK; Dandekar S
  • Start Page

  • 19593
  • End Page

  • 19604
  • Volume

  • 285
  • Issue

  • 25