Inflammation anergy in human intestinal macrophages is due to Smad-induced IκBα expression and NF-κB inactivation

Lesley E. Smythies, Ruizhong Shen, Diane Bimczok, Lea Novak, Ronald H. Clements, Devin E. Eckhoff, Phillipe Bouchard, Michael D. George, William K. Hu, Satya Dandekar, Phillip D. Smith

Research output: Contribution to journalArticle

124 Scopus citations

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 β, which together mediate all TLR MyD88-dependent and -independent NF-κB signaling, did not phosphorylate NF-κB p65 or Smad-induced IκBα, and did not translocate NF-κB into the nucleus. Importantly, transforming growth factor-β released from intestinal extracellular matrix (stroma) induced identical down-regulation in the NF-κB signaling and function of blood monocytes, the exclusive source of intestinal macrophages. Our findings implicate stromal transforming growth factor-β-induced dysregulation of NF-κB proteins and Smad signaling in the differentiation of pro-inflammatory blood monocytes into noninflammatory intestinal macrophages.

Original languageEnglish (US)
Pages (from-to)19593-19604
Number of pages12
JournalJournal of Biological Chemistry
Volume285
Issue number25
DOIs
StatePublished - Jun 18 2010

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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    Smythies, L. E., Shen, R., Bimczok, D., Novak, L., Clements, R. H., Eckhoff, D. E., Bouchard, P., George, M. D., Hu, W. K., Dandekar, S., & Smith, P. D. (2010). Inflammation anergy in human intestinal macrophages is due to Smad-induced IκBα expression and NF-κB inactivation. Journal of Biological Chemistry, 285(25), 19593-19604. https://doi.org/10.1074/jbc.M109.069955