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

118 Citations (Scopus)

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

Fingerprint

Macrophages
Toll-Like Receptors
Inflammation
Down-Regulation
Transforming Growth Factors
Cytokines
Tissue homeostasis
Monocytes
Blood
Myeloid Differentiation Factor 88
Smad Proteins
Interleukin-1 Receptors
Interferons
Extracellular Matrix
Mucous Membrane
Homeostasis
Ligands

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Smythies, L. E., Shen, R., Bimczok, D., Novak, L., Clements, R. H., Eckhoff, D. E., ... 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

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 journalArticle

Smythies, LE, Shen, R, Bimczok, D, Novak, L, Clements, RH, Eckhoff, DE, Bouchard, P, George, MD, Hu, WK, Dandekar, S & Smith, PD 2010, 'Inflammation anergy in human intestinal macrophages is due to Smad-induced IκBα expression and NF-κB inactivation', Journal of Biological Chemistry, vol. 285, no. 25, pp. 19593-19604. https://doi.org/10.1074/jbc.M109.069955
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. / Inflammation anergy in human intestinal macrophages is due to Smad-induced IκBα expression and NF-κB inactivation. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 25. pp. 19593-19604.
@article{b647f630ad2b4a2893df51307f9c8e45,
title = "Inflammation anergy in human intestinal macrophages is due to Smad-induced IκBα expression and NF-κB inactivation",
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.",
author = "Smythies, {Lesley E.} and Ruizhong Shen and Diane Bimczok and Lea Novak and Clements, {Ronald H.} and Eckhoff, {Devin E.} and Phillipe Bouchard and George, {Michael D.} and Hu, {William K.} and Satya Dandekar and Smith, {Phillip D.}",
year = "2010",
month = "6",
day = "18",
doi = "10.1074/jbc.M109.069955",
language = "English (US)",
volume = "285",
pages = "19593--19604",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "25",

}

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 -