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Tumor necrosis factor (TNF) alpha increases collagen accumulation and proliferation in intestinal myofibroblasts via TNF receptor 2.
J Biol Chem. 2005 Oct 28; 280(43):36099-109.JB

Abstract

Intestinal fibrosis is an incurable complication of Crohn's disease involving increased numbers of collagen-producing myofibroblasts. Tumor necrosis factor (TNF) alpha has defined proinflammatory roles in Crohn's disease but its role in fibrosis is unclear. We tested the hypothesis that TNFalpha increases collagen accumulation and proliferation in intestinal myofibroblasts and has additive effects in combination with insulin-like growth factor (IGF) I. The mechanisms, TNF receptor isoform, and downstream signaling pathways were examined. Intestinal myofibroblasts from wild-type (WT) mice or mice homozygous for disruption of genes encoding TNFR1 (TNFR1-/-), TNFR2 (TNFR2-/-), or both (TNFR1/2-/-), were treated with TNFalpha, IGF-I, or both. In WT cells, TNFalpha and IGF-I stimulated type I collagen accumulation and DNA synthesis in an additive manner. IGF-I, but not TNFalpha, stimulated type I collagen gene activation. TNFalpha, but not IGF-I, induced tissue inhibitor of metalloproteinase-1 (TIMP-1) expression and reduced matrix metalloproteinases-2 activity and collagen degradation. TNFalpha also activated ERK1/2. These responses to TNFalpha were absent in TNFR2-/- and TNFR1/2-/- myofibroblasts, whereas TNFR1-/- cells showed similar responses to WT. Inhibition of ERK1/2 diminished TNFalpha induced DNA synthesis in WT and TNFR1-/- cells. Differences in TNFalpha-induced STAT3/DNA binding activity and not NFkappaB and AP-1 transcriptional activation correlated with impaired collagen accumulation/TIMP-1 induction in TNFR2(-/-) cells. Constitutively active STAT3 rescued TIMP-1 expression in TNFR2-/- cells. We conclude that TNFalpha and IGF-I may additively contribute to fibrosis during intestinal inflammation. TNFR2 is a primary mediator of fibrogenic actions of TNFalpha acting through ERK1/2 to stimulate proliferation and through STAT3 to stimulate TIMP-1 and inhibit collagen degradation.

Authors+Show Affiliations

Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

16141211

Citation

Theiss, Arianne L., et al. "Tumor Necrosis Factor (TNF) Alpha Increases Collagen Accumulation and Proliferation in Intestinal Myofibroblasts Via TNF Receptor 2." The Journal of Biological Chemistry, vol. 280, no. 43, 2005, pp. 36099-109.
Theiss AL, Simmons JG, Jobin C, et al. Tumor necrosis factor (TNF) alpha increases collagen accumulation and proliferation in intestinal myofibroblasts via TNF receptor 2. J Biol Chem. 2005;280(43):36099-109.
Theiss, A. L., Simmons, J. G., Jobin, C., & Lund, P. K. (2005). Tumor necrosis factor (TNF) alpha increases collagen accumulation and proliferation in intestinal myofibroblasts via TNF receptor 2. The Journal of Biological Chemistry, 280(43), 36099-109.
Theiss AL, et al. Tumor Necrosis Factor (TNF) Alpha Increases Collagen Accumulation and Proliferation in Intestinal Myofibroblasts Via TNF Receptor 2. J Biol Chem. 2005 Oct 28;280(43):36099-109. PubMed PMID: 16141211.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tumor necrosis factor (TNF) alpha increases collagen accumulation and proliferation in intestinal myofibroblasts via TNF receptor 2. AU - Theiss,Arianne L, AU - Simmons,James G, AU - Jobin,Christian, AU - Lund,P Kay, Y1 - 2005/09/01/ PY - 2005/9/6/pubmed PY - 2006/1/5/medline PY - 2005/9/6/entrez SP - 36099 EP - 109 JF - The Journal of biological chemistry JO - J Biol Chem VL - 280 IS - 43 N2 - Intestinal fibrosis is an incurable complication of Crohn's disease involving increased numbers of collagen-producing myofibroblasts. Tumor necrosis factor (TNF) alpha has defined proinflammatory roles in Crohn's disease but its role in fibrosis is unclear. We tested the hypothesis that TNFalpha increases collagen accumulation and proliferation in intestinal myofibroblasts and has additive effects in combination with insulin-like growth factor (IGF) I. The mechanisms, TNF receptor isoform, and downstream signaling pathways were examined. Intestinal myofibroblasts from wild-type (WT) mice or mice homozygous for disruption of genes encoding TNFR1 (TNFR1-/-), TNFR2 (TNFR2-/-), or both (TNFR1/2-/-), were treated with TNFalpha, IGF-I, or both. In WT cells, TNFalpha and IGF-I stimulated type I collagen accumulation and DNA synthesis in an additive manner. IGF-I, but not TNFalpha, stimulated type I collagen gene activation. TNFalpha, but not IGF-I, induced tissue inhibitor of metalloproteinase-1 (TIMP-1) expression and reduced matrix metalloproteinases-2 activity and collagen degradation. TNFalpha also activated ERK1/2. These responses to TNFalpha were absent in TNFR2-/- and TNFR1/2-/- myofibroblasts, whereas TNFR1-/- cells showed similar responses to WT. Inhibition of ERK1/2 diminished TNFalpha induced DNA synthesis in WT and TNFR1-/- cells. Differences in TNFalpha-induced STAT3/DNA binding activity and not NFkappaB and AP-1 transcriptional activation correlated with impaired collagen accumulation/TIMP-1 induction in TNFR2(-/-) cells. Constitutively active STAT3 rescued TIMP-1 expression in TNFR2-/- cells. We conclude that TNFalpha and IGF-I may additively contribute to fibrosis during intestinal inflammation. TNFR2 is a primary mediator of fibrogenic actions of TNFalpha acting through ERK1/2 to stimulate proliferation and through STAT3 to stimulate TIMP-1 and inhibit collagen degradation. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/16141211/Tumor_necrosis_factor__TNF__alpha_increases_collagen_accumulation_and_proliferation_in_intestinal_myofibroblasts_via_TNF_receptor_2_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(20)59411-8 DB - PRIME DP - Unbound Medicine ER -