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J. Biol. Chem., Vol. 280, Issue 43, 36099-36109, October 28, 2005

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Tumor Necrosis Factor (TNF) Increases Collagen Accumulation and Proliferation in Intestinal Myofibroblasts via TNF Receptor 2^*

Arianne L. Theiss, James G. Simmons, Christian Jobin, and P. Kay Lund¶1

From the Departments of Cell and Molecular Physiology, ^¶Pediatrics, and Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina 27599

Intestinal fibrosis is an incurable complication of Crohn's disease involving increased numbers of collagen-producing myofibroblasts. Tumor necrosis factor (TNF) has defined proinflammatory roles in Crohn's disease but its role in fibrosis is unclear. We tested the hypothesis that TNF 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 TNF, IGF-I, or both. In WT cells, TNF and IGF-I stimulated type I collagen accumulation and DNA synthesis in an additive manner. IGF-I, but not TNF, stimulated type I collagen gene activation. TNF, but not IGF-I, induced tissue inhibitor of metalloproteinase-1 (TIMP-1) expression and reduced matrix metalloproteinases-2 activity and collagen degradation. TNF also activated ERK1/2. These responses to TNF were absent in TNFR2^–/– and TNFR1/2^–/– myofibroblasts, whereas TNFR1^–/– cells showed similar responses to WT. Inhibition of ERK1/2 diminished TNF induced DNA synthesis in WT and TNFR1^–/– cells. Differences in TNF-induced STAT3/DNA binding activity and not NFB 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 TNF and IGF-I may additively contribute to fibrosis during intestinal inflammation. TNFR2 is a primary mediator of fibrogenic actions of TNF acting through ERK1/2 to stimulate proliferation and through STAT3 to stimulate TIMP-1 and inhibit collagen degradation.

Received for publication, May 13, 2005 , and in revised form, August 23, 2005.

^* This work was supported by National Institutes of Health Grants R01-DK-47769 and R01-DK-40247 (to P. K. L.) and core facilities were supported by Lineberger Cancer Center Grant CA 16086 and Center for Gastrointestinal Biology and Disease Grant P30-DK-34987. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 919-966-1490; Fax: 919-966-6927; E-mail: empk{at}med.unc.edu.

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