title: CD40 ligand (CD40L) does not stimulate proliferation of vascular smooth muscle cells.
abstract: The present study investigates the effects of CD40 ligand (CD40L) on mitogenic signalling, proliferation, and migration of cultured bovine coronary artery smooth muscle cells (SMC). A time- and concentration-dependent phosphorylation of the extracellular signal-regulated kinases-1/2 (ERK-1/2) and the mitogen-activated protein kinase p38 (p38-MAPK) was observed upon stimulation with soluble CD40L (sCD40L). This phosphorylation was inhibited by neutralizing antibodies against the CD40 and CD40L, respectively. Activation of the phosphatidylinositol-3-phosphate (PI-3) kinase pathway by sCD40L, as determined by the measurement of Akt phosphorylation, was not detected. However, there was evidence for direct activation of the NFkappaB system (degradation of IkappaBalpha and nuclear translocation of the p65 NFkappaB subunit) by sCD40L. Accordingly, sCD40L caused a small but significant increase in DNA synthesis. However, sCD40L-induced DNA synthesis was not followed by proliferation (increase in cell number). Furthermore, sCD40L did not potentiate SMC mitogenesis induced by known mitogens such as platelet-derived growth factor-BB, thrombin or serum. The lack of cell proliferation was not caused by a concomitant induction of SMC apoptosis by sCD40L. The possible role of membrane-bound CD40L in SMC mitogenesis was also studied using different membrane preparations (platelets, lymphocytes). However, no mitogenic effects of membrane-bound CD40L were detected. Finally, sCD40L did not induce SMC migration. From these data it is concluded that CD40L activates mitogenic signalling and DNA synthesis but does not contribute to proliferation or migration of vascular SMC.
authors.affiliation: Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum Düsseldorf, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hermann
authors.forename: Karsten
authors.initials: K
authors.lastname: Schrör
authors.forename: Artur-Aron
authors.initials: AA
authors.lastname: Weber
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D002417:Cattle; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013859:Thiocarbamates / Q000494:pharmacology; D051996:Transcription Factor RelA
chemical_list: D000975:Antioxidants; D019013:CD40 Antigens; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D010982:Platelet-Derived Growth Factor; D011759:Pyrrolidines; D011993:Recombinant Fusion Proteins; D013859:Thiocarbamates; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D023201:CD40 Ligand; C020972:pyrrolidine dithiocarbamic acid; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases