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Inhibition of host connective tissue growth factor expression : a novel Trypanosoma cruzi-mediated response
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Unnikrishnan, Meera and Burleigh, Barbara A. (2004) Inhibition of host connective tissue growth factor expression : a novel Trypanosoma cruzi-mediated response. The FASEB Journal, Volume 18 (Number 14). pp. 1625-1635. doi:10.1096/fj.04-1554com
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Official URL: http://dx.doi.org/10.1096/fj.04-1554com
Abstract
Connective tissue growth factor (CTGF) is a secreted cytokine that plays a fundamental role in the development of tissue fibrosis by mediating many of the profibrotic effects of TGF-β. We present the novel finding that the intracellular pathogen Trypanosoma cruzi elicits immediate and sustained repression of basal CTGF expression in dermal fibroblasts, followed by down-regulation of the extracellular matrix proteins, fibronectin, and collagen I α1. To address mechanisms underlying this response, the major CTGF-regulating pathways were investigated. We report that both T. cruzi trypomastigotes and secreted parasite factor(s) antagonize TGF-β-dependent induction of CTGF in fibroblasts. Of the TGF-β-dependent signaling pathways required for CTGF expression, we demonstrate that T. cruzi interferes with cellular Erk1/2 phosphorylation but not Smad3 signaling. While increased stimulation of Erk phosphorylation alone was insufficient to override the parasite-mediated repression of CTGF, stimulation of fibroblasts with increased concentrations of TGF-β, which activates both Smad3 and Erk1/2, completely abrogated this inhibition. Together with the finding that T. cruzi-mediated down-regulation of CTGF expression requires de novo host cell protein synthesis, our data indicate that the unique ability of T. cruzi to interfere with the host fibrogenic response is a complex process requiring input from multiple host cell signaling pathways.—Unnikrishnan, M., Burleigh, B. A. Inhibition of host connective tissue growth factor expression: a novel Trypanosoma cruzi-mediated response.
| Item Type: | Journal Article | ||||
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| Subjects: | Q Science > QP Physiology | ||||
| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Microbiology & Infection Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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| Library of Congress Subject Headings (LCSH): | Trypanosoma cruzi, Extracellular matrix, Mitogen-activated protein kinases, Connective tissues -- Growth | ||||
| Journal or Publication Title: | The FASEB Journal | ||||
| Publisher: | Federation of American Societies for Experimental Biology | ||||
| ISSN: | 0892-6638 | ||||
| Official Date: | November 2004 | ||||
| Dates: |
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| Volume: | Volume 18 | ||||
| Number: | Number 14 | ||||
| Page Range: | pp. 1625-1635 | ||||
| DOI: | 10.1096/fj.04-1554com | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Restricted or Subscription Access | ||||
| Funder: | American Heart Association (AHA), National Institutes of Health (U.S.) (NIH), Burroughs Wellcome Fund (BWF) | ||||
| Grant number: | AI47960 and HL073227 (NIH) |
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