Selective upregulation of platelet-derived growth factor alpha receptors by transforming growth factor beta in scleroderma fibroblasts
نویسندگان
چکیده
Transforming growth factor beta (TGF-beta), a multifunctional cytokine, is an indirect mitogen for human fibroblasts through platelet-derived growth factor (PDGF), particularly the A ligand-alpha receptor arm of that system. TGF-beta effects on PDGF alpha receptor expression were studied in vitro using ligand binding techniques in three human dermal fibroblast strains: newborn foreskin, adult skin, and scleroderma (systemic sclerosis, SSc). Each cell strain responded differently to TGF-beta. In newborn foreskin fibroblasts, PDGF alpha receptor number decreased in a dose-dependent manner after exposure to low concentrations of TGF-beta (0.1-1 ng/ml). Responses of normal skin fibroblasts were varied, and mean net receptor number was unchanged. Increases in PDGF alpha receptor number by TGF-beta occurred consistently with SSc fibroblasts and low concentrations of TGF-beta (0.1-1 ng/ml) were particularly stimulatory. Increased surface expression of alpha receptor subunit by TGF-beta in SSc fibroblasts correlated with increased new PDGF alpha receptor synthesis as demonstrated by radioimmunoprecipitation analysis of metabolically labeled cells and with increased steady-state levels of corresponding mRNAs. In normal adult skin fibroblasts, TGF-beta had no effect on either synthesis or mRNA expression of alpha receptor subunits. Proliferative responses to PDGF-AA after pretreatment with TGF-beta correlated positively with effects of TGF-beta on expression of alpha receptor subunit. Decreased mitogenic responses to PDGF-AA were observed in foreskin fibroblasts, small changes in responses in adult fibroblasts, and significant increases in SSc fibroblasts. Thus, costimulation with PDGF-AA and TGF-beta selectively enhanced proliferation of fibroblasts with the SSc phenotype. Immunohistochemical examination of SSc and control skin biopsies revealed the presence of PDGF-AA in SSc skin. Data obtained by ligand binding, immunoprecipitation, mRNA, and mitogenic techniques are consistent with the hypothesis that activation of the PDGF-AA ligand/alpha receptor pathway is a characteristic of the SSc fibroblast and may contribute to the expansion of fibroblasts in SSc.
منابع مشابه
فاکتورهای رشد و پریودنتولوژی امروز
Growth factors are biological mediators that have a key roll in proliferation, chemotaxy and differentiation by acting on specific receptors on the surface of cells and regulating events in wound healing.They can be considered hormones that are not released in to the blood stream but have one a local action. Some of these factors can regulate premature change in GO to Gl phase in cell devesion ...
متن کاملTowards an anti-fibrotic therapy for scleroderma: targeting myofibroblast differentiation and recruitment
BACKGROUND In response to normal tissue injury, fibroblasts migrate into the wound where they synthesize and remodel new extracellular matrix. The fibroblast responsible for this process is called the myofibroblast, which expresses the highly contractile protein alpha-smooth muscle actin (alpha-SMA). In normal tissue repair, the myofibroblast disappears. Conversely, abnormal myofibroblast persi...
متن کاملMolecular aspects of scleroderma.
Scleroderma is a complex disease characterized by activation of the immune system, small-vessel vasculopathy, and fibrosis of the skin and other organs. This review is limited to the discussion of scleroderma fibroblast biology and the cellular and molecular mechanisms that contribute to the abnormal deposition of collagen. Selected aspects of abnormal extracellular matrix (ECM) regulation by s...
متن کاملTransforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts
Granulation tissue fibroblasts (myofibroblasts) develop several ultrastructural and biochemical features of smooth muscle (SM) cells, including the presence of microfilament bundles and the expression of alpha-SM actin, the actin isoform typical of vascular SM cells. Myofibroblasts have been proposed to play a role in wound contraction and in retractile phenomena observed during fibrotic diseas...
متن کاملSelective Upregulation of Platelet-derived Growth Factor c~ Receptors by Transforming Growth Factor/~ in Scleroder Fibroblasts
Transforming growth factor B (TGF-~), a multifunctional cytokine, is an indirect mitogen for human fibroblasts through platelet-derived growth factor (PDGF), particularly the A ligand-c~ receptor arm of that system. TGF-~ effects on PDGF ot receptor expression were studied in vitro using ligand binding techniques in three human dermal fibroblast strains: newborn foreskin, adult skin, and sclero...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- The Journal of Experimental Medicine
دوره 175 شماره
صفحات -
تاریخ انتشار 1992