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Cited by 60Connective Tissue Growth Factor ResearchChronic Kidney Disease and DiabetesCardiac Fibrosis and Remodeling

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

Cooker, Laurinda A., Peterson, Darryl, Rambow, Joann, Riser, Melisa L., Riser, Rebecca E., Najmabadi, Feridoon, Brigstock, David, Riser, Bruce L.·2007·American Journal of Physiology-Renal Physiology
DOI 10.1152/ajprenal.00508.2006
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Abstract

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.

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Crossref · 10.1152/ajprenal.00508.2006

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  • CCN1 expression is induced by inflammatory cytokines such as IL-1 and TNF-α.

    “CCN1 expression is induced by inflammatory cytokines such as IL-1 and TNF-α [33,131], as well as by bacterial and viral infections [29–32].”

    From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [131]

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Authors
Cooker, L. A., Peterson, D., Rambow, J., Riser, M. L., Riser, R. E., Najmabadi, F., Brigstock, D., & Riser, B. L.
Affiliations
Rosalind Franklin University of Medicine and Science (US)
ORCID
Brigstock, David
Venue
American Journal of Physiology-Renal Physiology
Publisher
American Physiological Society
Published
2007-07
Volume
293
Issue
1
Pages
F157-F165
ISSN
  • 1522-1466 (ISSN-L)
  • 1931-857X
DOI
10.1152/ajprenal.00508.2006
OpenAlex
W1967936536
Cited by
60
References
61
Citations by year
2026: 1 · 2025: 3 · 2024: 1 · 2022: 3 · 2021: 3 · 2019: 2 · 2018: 3 · 2016: 1 · 2015: 3 · 2014: 6 · 2013: 1 · 2012: 4
FWCI
3.04
Type
journal article
Language
en
Open access
closed
Locations
  • American Journal of Physiology-Renal Physiology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
  • Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
Keywords
TNF-α, interferon-gamma, connective tissue growth factor, type I collagen, mesangial cells, renal fibrosis, TGF-beta, glomerular fibrosis, cell proliferation, extracellular matrix, inflammation, cytokine synergy
MeSH terms
Animals, Cells, Cultured, Fibrosis, Glomerular Mesangium, Interferon-gamma, Kidney Diseases, Rats, Inbred F344, RNA, Messenger, Tumor Necrosis Factor-alpha, Blotting, Northern, Transforming Growth Factor beta, Immediate-Early Proteins, DNA, Complementary, Disease Progression, Collagen Type I, Intercellular Signaling Peptides and Proteins, Cell Proliferation, Rats, Connective Tissue Growth Factor

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