Cytokines and human fibrosis.
Cytokines are soluble informational polypeptides which modulate cellular functions by combining with specific membrane receptors in the originating cell (autocrine), a regional cell (paracrine) or a distant cell (endocrine). Cytokine-receptor complexes usually initiate signal transduction via protein kinase phosphorylation or G-protein dependent phospholinositol changes which further alter cell function. In the exuberant fibrosis of scleroderma, fibroblasts are activated to secrete several extracellular matrix molecules (collagens, fibronectin, proteoglycans) and they also fail to respond to the usual cell growth signals in vitro. We have studied the hypothesis that cytokines released through the T-cell dependent activation/injury of the vascular and microvascular endothelium initiate activation of the scleroderma fibroblast. Recalling that cell activation can occur either by removal of suppression or direct activation and that the locus of action can be transcriptional, translational or post-translational or a combination of these, our studies have focused on the cytokine transforming growth factor beta (TGF-beta) family of molecules, on the matrix gene expression abnormality of the scleroderma fibroblast and on the activation by TGF-beta of the platelet derived growth factor (PDGF) family of cytokines to explain the persistent cell growth abnormality. Our findings include: 1. Scleroderma fibroblasts are equally responsive to TGF-beta as are healthy fibroblasts with regard to collagen synthesis and they bind TGF-beta in all parameters similar to the binding to healthy fibroblasts. 2. TGF-beta is a stronger mitogenic signal to scleroderma fibroblasts than to control fibroblasts in the presence of serum.(ABSTRACT TRUNCATED AT 250 WORDS)
LeRoy
E C
EC
Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston 29420-2229.
Trojanowska
M I
MI
Smith
E A
EA
D002450:Cell Communication; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology*; D004730:Endothelium, Vascular / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology / Q000502:physiology; D008213:Lymphocyte Activation; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D017479:Receptors, Platelet-Derived Growth Factor; D012595:Scleroderma, Systemic / Q000276:immunology / Q000473:pathology*; D015398:Signal Transduction; D012867:Skin / Q000473:pathology; D013601:T-Lymphocytes / Q000473:pathology; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014945:Wound Healing / Q000502:physiology
D016207:Cytokines; D016326:Extracellular Matrix Proteins; D007376:Interleukin-2; D010982:Platelet-Derived Growth Factor; D011956:Receptors, Cell Surface; D016212:Transforming Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor