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Mesangial cell-matrix interactions. Effects on mesangial cell growth and cytokine secretion
C Ruef1, M Kashgarian, D L Coleman
1Department of Medicine, Yale University School of Medicine, New Haven, Connecticut.
Abstract:
Glomerulonephritis (GN) results in proliferation of mesangial cells (MC), infiltration of inflammatory cells, and accumulation of extracellular matrix (ECM) proteins in the mesangium. Locally secreted cytokines may stimulate MC growth or the secretion of inflammatory mediators by MC. Interleukin-6 (IL-6) may be an autocrine cofactor in the pathogenesis of mesangioproliferative GN. We studied the regulation of IL-6 secretion by MC in response to MC-derived cytokines and ECM proteins. IL-6 secretion is stimulated in a dose-dependent manner by IL-1 alpha, TNF-alpha, and PDGF. Constitutive and LPS-induced release of IL-6 by MCs is reduced on collagen type I (coll I) compared-with uncoated surfaces. IL-6 release on collagen type IV (coll IV), however, is enhanced. In addition, MC on coll I exhibit a sixfold higher growth rate than cells on uncoated surfaces. The reduction of cytokine secretion in parallel with the stimulation of MC growth by coll I suggests that exposure to coll I may result in a change from secretory to proliferative phenotype in vitro.
Insights
Glomerulonephritis involves mesangial cell proliferation and extracellular matrix accumulation. Collagen type I shifts mesangial cells from cytokine secretion to proliferation, impacting disease progression.
Area of Science:
- Nephrology
- Cell Biology
- Immunology
Background:
- Glomerulonephritis (GN) is characterized by mesangial cell (MC) proliferation, inflammatory cell infiltration, and extracellular matrix (ECM) accumulation.
- Locally secreted cytokines may influence MC growth and inflammatory mediator secretion.
- Interleukin-6 (IL-6) is implicated as an autocrine cofactor in mesangioproliferative GN pathogenesis.
Purpose of the Study:
- To investigate the regulation of IL-6 secretion by MC in response to MC-derived cytokines and ECM proteins.
- To understand the role of specific ECM components, collagen type I (coll I) and collagen type IV (coll IV), in MC behavior.
Main Methods:
- MC cultures were treated with cytokines (IL-1 alpha, TNF-alpha, PDGF) and cultured on uncoated surfaces, coll I, or coll IV.
- IL-6 secretion levels were measured.
- MC growth rates were assessed on different surfaces.
Main Results:
- IL-6 secretion was dose-dependently stimulated by IL-1 alpha, TNF-alpha, and PDGF.
- Collagen type I reduced both constitutive and LPS-induced IL-6 release, while enhancing MC growth sixfold compared to uncoated surfaces.
- Collagen type IV increased IL-6 release.
Conclusions:
- Collagen type I exposure induces a shift in MC phenotype from secretory to proliferative in vitro.
- Differential interactions with ECM proteins like collagen I and IV significantly modulate MC IL-6 secretion and growth, offering insights into mesangioproliferative GN mechanisms.