Platelets induce reactive oxygen species-dependent growth of human skin fibroblasts.
A growing amount of evidence suggests that reactive oxygen species (ROS), such as hydrogen peroxide and superoxide anion, regulate intracellular signalling and have a role in cell proliferation. In the present study, we show that platelets increase the mitogenic rate in human fibroblasts and that this effect was inhibited by the intracellular antioxidant N-acetyl-L-cysteine (NAC) and the NADPH-oxidase inhibitor diphenyleneiodonium chloride (DPI). The mitogenic effects of platelets were mimicked by the platelet factors platelet-derived growth factor BB-isoform (PDGF-BB), transforming growth factor beta1 (TGF-beta1) and sphingosine-1-phosphate (S1P). The sphingosine kinase inhibitor DL-threo-dihydrosphingosine (DL-dihydro) abrogated the platelet-induced growth, while antibodies directed against PDGF or TGF-beta had modest effects. Exposure of fibroblasts to platelets, PDGF-BB, TGF-beta1 or S1P caused an extensive intracellular ROS production, measured as changes in dichlorofluorescein fluorescence. This ROS production was totally inhibited by NAC, pyrrolidinethiocarbamate (PDTC), DPI and apocynin. In conclusion, the results presented are indicative of a crucial role of ROS in the platelet-mediated regulation of fibroblast proliferation.
Berg
Cecilia
C
Division of Medical Microbiology, Department of Molecular and Clinical Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden. cecbe@ifm.liu.se
Trofast
Catarina
C
Bengtsson
Torbjörn
T
D000098:Acetophenones / Q000494:pharmacology; D000111:Acetylcysteine / Q000494:pharmacology; D000077214:Becaplermin; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005452:Fluoresceins / Q000737:chemistry; D006801:Humans; D008246:Lysophospholipids / Q000037:antagonists & inhibitors / Q000494:pharmacology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D009861:Onium Compounds / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012867:Skin / Q000166:cytology / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
D000098:Acetophenones; D004791:Enzyme Inhibitors; D005452:Fluoresceins; D008246:Lysophospholipids; D009861:Onium Compounds; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D017382:Reactive Oxygen Species; C508960:TGFB1 protein, human; D013859:Thiocarbamates; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000077214:Becaplermin; C060506:sphingosine 1-phosphate; C037631:2',7'-dichlorofluorescein; C007517:diphenyleneiodonium; C056165:acetovanillone; D019255:NADPH Oxidases; D013110:Sphingosine; D000111:Acetylcysteine