TNF-α, but not IFN-γ, regulates CCN2 (CTGF), collagen type I, and proliferation in mesangial cells: possible roles in the progression of renal fibrosis
| Autor: | Laurinda A. Cooker, Rebecca E. Riser, Darryl R. Peterson, David Brigstock, Melisa L. Riser, Feridoon Najmabadi, Bruce L. Riser, Joann Rambow |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
medicine.medical_specialty
DNA Complementary Physiology Renal glomerulus medicine.medical_treatment Connective tissue Collagen Type I Immediate-Early Proteins Proinflammatory cytokine Interferon-gamma Transforming Growth Factor beta Fibrosis Internal medicine medicine Renal fibrosis Animals RNA Messenger Cells Cultured Cell Proliferation integumentary system Mesangial cell Tumor Necrosis Factor-alpha business.industry Growth factor Connective Tissue Growth Factor Blotting Northern medicine.disease Rats Inbred F344 Glomerular Mesangium Rats medicine.anatomical_structure Endocrinology Cytokine Disease Progression Intercellular Signaling Peptides and Proteins Kidney Diseases business |
| Zdroj: | American Journal of Physiology-Renal Physiology. 293:F157-F165 |
| ISSN: | 1522-1466 1931-857X |
| DOI: | 10.1152/ajprenal.00508.2006 |
| Popis: | Connective tissue growth factor (CCN2) is a profibrotic factor acting downstream and independently of TGF-beta 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-alpha and IFN-gamma, for their effects on cultured mesangial cells in the presence or absence of TGF-beta, as a model for progressive renal fibrosis. Short-term treatment with TNF-alpha, like TGF-beta, significantly increased secreted CCN2 per cell, but unlike TGF-beta inhibited cellular replication. TNF-alpha combined with TGF-beta further increased CCN2 secretion and mRNA levels and reduced proliferation. Surprisingly, however, TNF-alpha treatment decreased baseline collagen type I protein and mRNA levels and largely blocked their stimulation by TGF-beta. Long-term treatment with TGF-beta or TNF-alpha alone no longer increased CCN2 protein levels. However, the combination synergistically increased CCN2. IFN-gamma had no effect on either CCN2 or collagen activity and produced a mild inhibition of TGF-beta-induced collagen only at a high concentration (500 U/ml). In summary, we report a strong positive regulatory role for TNF-alpha, but not IFN-gamma, in CCN2 production and secretion, including that driven by TGF-beta. The stimulation of CCN2 release by TNF-alpha, unlike TGF-beta, is independent of cellular proliferation and not linked to increased collagen type I accumulation. This suggests that the paradigm of TGF-beta-driven CCN2 with subsequent collagen production may be overridden by an as yet undefined inhibitory mechanism acting either directly or indirectly on matrix metabolism. |
| Databáze: | OpenAIRE |
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