Inflammation anergy in human intestinal macrophages is due to Smad-induced IkappaBalpha expression and NF-kappaB inactivation.
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.
Smythies
Lesley E
LE
Department of Medicine Gastroenterology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA. lesmy@uab.edu.
Shen
Ruizhong
R
Bimczok
Diane
D
Novak
Lea
L
Clements
Ronald H
RH
Eckhoff
Devin E
DE
Bouchard
Phillipe
P
George
Michael D
MD
Hu
William K
WK
Dandekar
Satya
S
Smith
Phillip D
PD
D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D007249:Inflammation; D007413:Intestinal Mucosa / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D016207:Cytokines; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D000072000:NF-KappaB Inhibitor alpha
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