Mitogenic effect of platelet-derived growth factor in human glomerular mesangial cells: modulation and/or suppression by inflammatory cytokines

Abstract

SUMMARY Glomerular mesangial cell proliferation constitutes a frequent pathological alteration in glomerulonephritis. In addition to platelet-derived growth factor (PDGK) inflammatory cytokines such as IL-1. IL-6 or tumour necrosis factor-alpha (TNF-α) have been proposed to have mitogenic activity for mesangial cells. A model was therefore established in which human mesangial cells (HMC) could be reversibly growth-arrested for prolonged times in serum-free medium without suffering irreversible functional or morphological changes. In this model 24 h stimulation with rhPDGF-BB induced an increase of the 3H-thymidine incorporation of 1190.280 (50 ng/ml) %± s.e.m. of medium control. Less growth induction was noted after stimulation with 50 ng ml rhPDGF-AB (925± I26) or rhPDGF-AA (575 ± 24%). Northern analysis confirmed the presence of both α and β-PDGF receptor subunit mRNA in growth-arrested HMCs. rhlL-lα, rhlL-1β, rhTNF-α or rhIL-6 at various doses and times, despite increasing cellular PGE2-release, did not induce significant proliferation in HMCs. Inhibition of PGE2-release did not change the lack ol mitogenicity of lL-l, TNF-α or lL-6. IL-6 did not alter the mitogenic response of the cells towards PDGF. In contrast, both IL-lα and lL-lβ (5 ng/ml) induced a delay but not augmentation of the PDGF growth response. This delay could be reversed by the concomitant addition or recombinant IL-6 or of anti-lL-1 antibody but not by inhibition of prostaglandin synthesis. High doses of TNF-α suppressed PDGF-induced proliferation. These data suggest that in growth-arrested HMCs inflammatory cytokines have a growth-modulating or -suppressive rather than (co-)mitogenic effect while PDGF-BB and-AB and to a lesser degree PDGF-AA are potent mitogens. The findings support the notion that the control of HMC proliferation in pathological situations depends on a complex network of interacting stimuli.