Mitogenic effect of platelet-derived growth factor in human glomerular mesangial cells: modulation and/or suppression by inflammatory cytokines.
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.
Floege
J
J
Department of Nephrology, Medizinische Hochschule Hannover, Germany.
Topley
N
N
Hoppe
J
J
Barrett
T B
TB
Resch
K
K
D015152:Blotting, Northern; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival; D016895:Culture Media, Serum-Free; D016207:Cytokines / Q000494:pharmacology*; D015870:Gene Expression; D005920:Glomerular Mesangium / Q000166:cytology*; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000503:physiopathology; D007378:Interleukins / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics; D017479:Receptors, Platelet-Derived Growth Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016895:Culture Media, Serum-Free; D016207:Cytokines; D007378:Interleukins; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D017479:Receptors, Platelet-Derived Growth Factor