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Inhibition of host connective tissue growth factor expression: a novel Trypanosoma cruzi ‐mediated response
Author(s) -
Unnikrishnan Meera,
A. Burleigh Barbara
Publication year - 2004
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-1554com
Subject(s) - ctgf , microbiology and biotechnology , growth factor , signal transduction , trypanosoma cruzi , biology , fibronectin , connective tissue , transforming growth factor beta , mapk/erk pathway , transforming growth factor , extracellular matrix , cyr61 , cell signaling , extracellular , receptor , biochemistry , parasite hosting , genetics , world wide web , computer science
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. FASEB J. 18, 1625–1635 (2004)