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This Article Full Text Full Text (PDF) All Versions of this Article: 293/1/F157    most recent 00508.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Cooker, L. A. Articles by Riser, B. L. Search for Related Content PubMed PubMed Citation Articles by Cooker, L. A. Articles by Riser, B. L.

TNF-, but not IFN-, regulates CCN2 (CTGF), collagen type I, and proliferation in mesangial cells: possible roles in the progression of renal fibrosis

¹Department of Physiology and Biophysics, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois; ²Center for Cell and Vascular Biology, Children's Research Institute, Columbus, Ohio; and ³Baxter Healthcare, Renal Division, McGaw Park, Illinois

Submitted 19 December 2006 ; accepted in final form 13 March 2007

Connective tissue growth factor (CCN2) is a profibrotic factor acting downstream and independently of TGF- to mediate renal fibrosis. Although inflammation is often involved in the initiation and/or progression of fibrosis, the role of inflammatory cytokines in regulation of glomerular CCN2 expression, cellular proliferation, and extracellular matrix accumulation is unknown. We studied two such cytokines, TNF- and IFN-, for their effects on cultured mesangial cells in the presence or absence of TGF-, as a model for progressive renal fibrosis. Short-term treatment with TNF-, like TGF-, significantly increased secreted CCN2 per cell, but unlike TGF- inhibited cellular replication. TNF- combined with TGF- further increased CCN2 secretion and mRNA levels and reduced proliferation. Surprisingly, however, TNF- treatment decreased baseline collagen type I protein and mRNA levels and largely blocked their stimulation by TGF-. Long-term treatment with TGF- or TNF- alone no longer increased CCN2 protein levels. However, the combination synergistically increased CCN2. IFN- had no effect on either CCN2 or collagen activity and produced a mild inhibition of TGF--induced collagen only at a high concentration (500 U/ml). In summary, we report a strong positive regulatory role for TNF-, but not IFN-, in CCN2 production and secretion, including that driven by TGF-. The stimulation of CCN2 release by TNF-, unlike TGF-, is independent of cellular proliferation and not linked to increased collagen type I accumulation. This suggests that the paradigm of TGF--driven CCN2 with subsequent collagen production may be overridden by an as yet undefined inhibitory mechanism acting either directly or indirectly on matrix metabolism.

inflammatory cytokines; chronic kidney disease; pathophysiology of renal disease