The 80-kD fibronectin fragment increases the production of fibronectin and tumour necrosis factor-alpha (TNF-alpha) in cultured mesangial cells.
The presence of fibronectin (FN) fragments has been demonstrated in several inflammatory processes, and they have been implicated in the recruitment of mononuclear cells. However, the interaction of these FN fragments with resident cells has hardly been studied. We have hypothesized that the 80-kD FN fragment, which includes the RGD cell binding domain of FN, could contribute to the pathogenesis of glomerular damage through the interaction with mesangial cells (MC) via alpha5beta1 integrin. Since an increase in the glomerular deposit of matrix components, particularly FN, is frequently observed in progressive glomerulonephritis, we studied whether its synthesis is modulated by the 80-kD FN fragment and the native FN molecule. While the 80-kD FN fragment stimulated FN in a dose-dependent manner, both at the mRNA and protein level, the whole FN molecule exerted a dual effect. High doses produced FN inhibition, while low doses elicited a certain increase. This stimulation was abrogated by the presence of Sam-1, a MoAb against the alpha-subunit of the alpha5beta1 integrin. Since cytokines play a fundamental role in glomerular injury, we studied the production of TNF-alpha, one of the most powerful mediators of inflammation. TNF-alpha synthesis was induced by the 80-kD FN fragment, in a dose-dependent manner, but not by native FN. When MC were incubated with the 29- and 31-kD FN fragments, which lack the RGD cell binding domain, TNF-alpha secretion was not detected. These results strongly suggest that in cultured MC, the 80-kD FN fragment induces the synthesis of matrix proteins such as FN, and cytokines such as TNF-alpha, via alpha5beta1 integrin. This mechanism could contribute to the perpetuation of renal injury.
Lopez-Armada
M J
MJ
Renal Research Laboratory, Fundación Jiménez Diáz, Universidad Autónoma, Madrid, Spain.
Gonzalez
E
E
Gomez-Guerrero
C
C
Egido
J
J
D000818:Animals; D002478:Cells, Cultured; D005353:Fibronectins / Q000096:biosynthesis*; D005920:Glomerular Mesangium / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017469:Receptors, Fibronectin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D005353:Fibronectins; D010446:Peptide Fragments; D017469:Receptors, Fibronectin; D014409:Tumor Necrosis Factor-alpha