Connective tissue growth factor (CCN2) is a profibrotic factor acting downstream and independently of TGF-β 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-α and IFN-γ, for their effects on cultured mesangial cells in the presence or absence of TGF-β, as a model for progressive renal fibrosis. Short-term treatment with TNF-α, like TGF-β, significantly increased secreted CCN2 per cell, but unlike TGF-β inhibited cellular replication. TNF-α combined with TGF-β further increased CCN2 secretion and mRNA levels and reduced proliferation. Surprisingly, however, TNF-α treatment decreased baseline collagen type I protein and mRNA levels and largely blocked their stimulation by TGF-β. Long-term treatment with TGF-β or TNF-α alone no longer increased CCN2 protein levels. However, the combination synergistically increased CCN2. IFN-γ had no effect on either CCN2 or collagen activity and produced a mild inhibition of TGF-β-induced collagen only at a high concentration (500 U/ml). In summary, we report a strong positive regulatory role for TNF-α, but not IFN-γ, in CCN2 production and secretion, including that driven by TGF-β. The stimulation of CCN2 release by TNF-α, unlike TGF-β, is independent of cellular proliferation and not linked to increased collagen type I accumulation. This suggests that the paradigm of TGF-β-driven CCN2 with subsequent collagen production may be overridden by an as yet undefined inhibitory mechanism acting either directly or indirectly on matrix metabolism.
IP-10 and Mig Production by Glomerular Cells in Human Proliferative Glomerulonephritis and Regulation by Nitric Oxide
