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

Clin Exp Immunol. 1991 Nov;86(2):334-41. doi: 10.1111/j.1365-2249.1991.tb05819.x.

Abstract

Glomerular mesangial cell proliferation constitutes a frequent pathological alteration in glomerulonephritis. In addition to platelet-derived growth factor (PDGF) inflammatory cytokines such as IL-1, IL-6 or tumour necrosis factor-alpha (TNF-alpha) 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 +/- 126%) or rhPDGF-AA (575 +/- 24%). Northern analysis confirmed the presence of both alpha- and beta-PDGF receptor subunit mRNA in growth-arrested HMCs. rhIL-1 alpha, rhIL-1 beta, rhTNF-alpha 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 of mitogenicity of IL-1, TNF-alpha or IL-6. IL-6 did not alter the mitogenic response of the cells towards PDGF. In contrast, both IL-1 alpha and IL-1 beta (5 ng/ml) induced a delay but not augmentation of the PDGF growth response. This delay could be reversed by the concomitant addition of recombinant IL-6 or of anti-IL-1 antibody but not by inhibition of prostaglandin synthesis. High doses of TNF-alpha 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Blotting, Northern
  • Cell Division / drug effects
  • Cell Survival
  • Culture Media, Serum-Free
  • Cytokines / pharmacology*
  • Gene Expression
  • Glomerular Mesangium / cytology*
  • Humans
  • In Vitro Techniques
  • Inflammation / physiopathology
  • Interleukins / pharmacology
  • Platelet-Derived Growth Factor / antagonists & inhibitors
  • Platelet-Derived Growth Factor / pharmacology*
  • RNA, Messenger / genetics
  • Receptors, Cell Surface / genetics
  • Receptors, Platelet-Derived Growth Factor
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Culture Media, Serum-Free
  • Cytokines
  • Interleukins
  • Platelet-Derived Growth Factor
  • RNA, Messenger
  • Receptors, Cell Surface
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • Receptors, Platelet-Derived Growth Factor