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 language | English (US) |
|---|---|
| Pages (from-to) | 19593-19604 |
| Number of pages | 12 |
| Journal | Journal of Biological Chemistry |
| Volume | 285 |
| Issue number | 25 |
| DOIs | |
| State | Published - Jun 18 2010 |
Fingerprint
ASJC Scopus subject areas
- Biochemistry
- Cell Biology
- Molecular Biology
Cite this
Inflammation anergy in human intestinal macrophages is due to Smad-induced IκBα expression and NF-κB inactivation. / Smythies, Lesley E.; Shen, Ruizhong; Bimczok, Diane; Novak, Lea; Clements, Ronald H.; Eckhoff, Devin E.; Bouchard, Phillipe; George, Michael D.; Hu, William K.; Dandekar, Satya; Smith, Phillip D.
In: Journal of Biological Chemistry, Vol. 285, No. 25, 18.06.2010, p. 19593-19604.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Inflammation anergy in human intestinal macrophages is due to Smad-induced IκBα expression and NF-κB inactivation
AU - Smythies, Lesley E.
AU - Shen, Ruizhong
AU - Bimczok, Diane
AU - Novak, Lea
AU - Clements, Ronald H.
AU - Eckhoff, Devin E.
AU - Bouchard, Phillipe
AU - George, Michael D.
AU - Hu, William K.
AU - Dandekar, Satya
AU - Smith, Phillip D.
PY - 2010/6/18
Y1 - 2010/6/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=77953482525&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77953482525&partnerID=8YFLogxK
U2 - 10.1074/jbc.M109.069955
DO - 10.1074/jbc.M109.069955
M3 - Article
C2 - 20388715
AN - SCOPUS:77953482525
VL - 285
SP - 19593
EP - 19604
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 25
ER -