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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

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