Systemic sclerosis (scleroderma) is characterized by excessive fibroblastic activity taking place through mechanisms largely unknown. It has been speculated that soluble factors, collectively categorized as lymphokines or monokines, and released by inflammatory or other differentiated cells, may modulate fibroblast multiple functions including migration, chemotaxis and protein synthesis. Vascular endothelium itself, which is deeply injured in systemic sclerosis, is acting as a target for the action of cytokines and is an important producer of polypeptide mediators that contribute to the inflammatory reaction and to the establishment of fibrosis. Thus, interactions through soluble mediators between fibroblasts, endothelial cells and immunocompetent cells appear crucial for the development of systemic sclerosis lesions. The aim of the present study is to evaluate the available information on the role of cytokines and to discuss their potential influence in the pathogenesis of systemic sclerosis.
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References
1.
WinkelmannR.K.1986. Pathogenesis and staging of scleroderma. Acta Derm. Venereal.56:83.
2.
LeRoyE.C.1981. Scleroderma (Systemic sclerosis). In Textbook of Rheumatology. KelleyW. B.HarrisE. D.RuffyS.HedgeL. B., W.B. Saunders, Philadelphia/ NewYork/ Toronto. p 1121.
3.
SacknerM.A.1966. Scleroderma. Grune Stratton, New York.
4.
LeRoyE.C.1972. Connective tissue synthesis by scleroderma skin fibroblasts in cell culture. J. Exp. Med.135:1351.
5.
PostlethwaiteA.E.RaghowR.StricklinG.P.PoppletonH.SeyerJ.M.KangA.H.1988. Modulation of fibroblast function by interleukin-1: Increased steady-state accumulation of type procollagen mRNAs and stimulation of other function but not chemotaxis by human recombinant interleukin 1 and α β. J. Cell. Biol.106:311.
6.
GoldringM.B.KraneS.M.1987. Modulation by recombinant interleukin 1 of synthesis of types I and III collagen and associated procollagen mRNAs levels in cultured human cells. J. Biol. Chem.262:16724.
7.
RainesE.W.DowerS.K.RossR.1989. Interleukin 1 mitogenic activity for fibroblasts and smooth muscle cells is due to PDGF-AA. Science243:393.
8.
BussolinoF.BreviarioF.TettaC.1986. Interleukin-1 stimulates platelet-activating factor production in cultured human endothelial cellsJ. Clin. Invest.77:2027.
9.
BevilacquaM.P.SchleefR.R.GimbroneM.A.Jr.LoskutoffD.J., 1986. Regulation of the fibrinolytic system of cultured human vascular endothelium by interleukin 1. J. Clin. Invest.78:587.
10.
NachmanR.L.HajjarK.A.SilversteinR.L.DinarelloC.A., 1986. Interleukin 1 induces endothelial cell synthesis of plasminogen activator inhibitor. J. Exp. Med.163:1595.
11.
EmeisJ.J.KooistraJ., 1986. Interleukin 1 and lipopolysaccharide induce an inhibitor of tissue-type plasminogen activator in vivo and in cultured endothelial cells. J. Exp. Med.163:1260.
12.
GramseM.BreviarioF.PintucciG.1986. Enhancement by interleukin 1 (IL-1) of plasminogen activator inhibitor (PA-1) activity in cultured human endothelial cells. Biochem. Biophys. Res. Commun.139:720.
13.
BevilacquaM.P.StengelinS.GimbroneM.A.Jr.SeedB., 1989. Endothelial leukocytes adhesion molecule 1: An inducible receptor for neutrophils related to complement regulatory proteins and lectins. Science243:1160.
MassagueJ.1987. The TGFβ1 family of growth differentiation factors. Cell49:437.
16.
Keski-OjaJ.LyonsR.M.MosesH.L.1987. Inactive secreted form of transforming growth factor β: Activation by proteolysis. J. Cell Biochem. (Suppl.)11A:60.
17.
PostlethwaiteA.E.Keski-OjaJ.MosesH.L.KangA.H., 1987. Stimulation of the chemotactic migration of human fibroblasts by transforming growth factor β. J. Exp. Med.165:251.
18.
IgnotzR.A.MassagueJ.1986. Transforming growth factor β stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J. Biol. Chem.261:4337.
19.
RaghowR.PostlethwaiteA.E.Kesli-OjaJ.MoseH.L.Q.KangA.H.1987. Transforming growth factor β increses steady-state levels of type procollagen and fibronectin messanger RNAs post-transcriptionally in cultured human dermal fibroblasts. J. Clin. Invest.79:1285.
20.
VargaJ.RosenbloomJ.JimenezA.1987. Transforming growth factor β (TGF β) causes a persistent increase in steady-state amounts of type I and type III collagen and fibronectin mRNAs in normal human fibroblasts. Biochem. J.247:597.
21.
MoesH.L.CoffeyR.J.LeofE.B.LyousandR.M.Keski-OjaJ.1987. Transforming growth factor β regulation of cell proliferation. J. Cell Physiol. (Suppl)5: 1.
22.
RobertsA.B.SpornM.B.AssoianR.K.SmithJ.M.RocheN.S.WakefieldL.M.HeineU.I.LiottaL.A.FalangaV.XehrlJ.H.FauciA.S.A.1986. Transforming growth factor: Rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc. Natl. Acad. Sci (USA)83: 4167.
23.
MadriJ.A.PrattB.M.B.TuckerA.M.1988. Phenotypic modulation of endothelial cells by transforming growth factor β depends upon the composition and organization of the extracellular matrix. J. Cell Biol. 106:1375.
24.
TakeharaK.LeRoyE.C.GrotendorstG.R.1987. TGFβ inhibition of endothelial cell proliferation: Alteration of EGF binding and EGF induced growth-regulatory (competence) gene expression. Cell49:415.
25.
KehrlJ.H.WakefieldL.M.RobertsA.B.JakowlewS.Alvarez-MonM.DerynckR.SpornM.B.M.B.FauciA.S., 1986. Production of transforming growth factor β by human T lymphocytes and its potential role in the regulation of T cell growth. J. Exp. Med.163:1037.
26.
GruschwitzM.MullerP.U.SeppN.HoferE.FontanaM.WickG.1990. Transcription and expression of transforming growth factor type in the skin of progressive systemic sclerosis: A mediator of fibrosis?J. Clin. Invest.94:197.
27.
PeltonenJ.KahariL.JaakkolaS.KahariV.M.VargaJ.VittoJ.JimenezS.1990. Evaluation of transforming growth factor β and type I procollagen gene expression in fibrotic skin diseases by in situ hybridization. J. Invest. Dermatol.94:365.
28.
GabrielliA.Di LoretoC.TaborroR.CandelaM.RicciattiA.M.NittiC.DanieliM.G.DeLustroF.DanieliG.Immunohistochemical localization of active and latent form of TGF β in the skin of patients with systemic sclerosis (scleroderma) and primary Raynaud's phenomenon. Submitted.
29.
RossR.RainesE.W.Bowen-PopeD.F.1986. The biology of platelet-derived growth factor. Cell46:155.
30.
SeppaH.GrotendorstG.SeppaS.SchiffmannE.E.MartinG.R., 1982. The platelet-derived growth factor is chemotactic for fibroblasts. J. Cell Biol. 92:584.
31.
BarbulA.HuntT.K., 1988. Growth factors and other aspects of normal healing: Biological and clinical implications. AR Liss Inc, New York.
32.
ShinokadoK.RainesE.W.MadtesD.K.BarrettT.B.BendittE.P.RossR., 1985. A significant part of macrophage-derived growth factor consists of at least two forms of PDGF. Cell43:277.
33.
Di CarletoP.E.Bowen-PopeD.F., 1983. Cultured endothelial cells produce a platelet-derived growth factor-like protein. Proc. Natl. Acad. Sci (USA)80: 1919.
34.
LibbyP.WarnerS.J.C.SalomonR.N.BirinyiL.K., 1988. Production of platelet-derived growth factor-like mitogen by smooth muscle cells from human atheroma. N. Engl. J. Med.318:1493.
35.
MartinetY.RomW.N.GrotendorstG.R.MartinG.R.CrystalR.G., 1987. Exaggerated spontaneous release of platelet-derived growth factor by alveolar macrophages from patients with idiopathic pulmonary fibrosis. N. Engl. J. Med.317:202.
36.
SugarmanB.J.AggarwalB.B.HassP.E.FigariI.S.PalladinoM.A.Jr.ShepardH.M.H.M.1985. Recombinant human tumor necrosis factor: α effect on proliferation of normal and transformed cells in vitro. Science230:943.
37.
VilcekJ.PalombellaV.J.Henriksen-DeStefanoD.SwensonC.FeinmanR.HiraiM.TsujimotoM., 1986. Fibroblast growth-enhancing activity of tumor necrosis factor and its relationship to other polypeptide growth factors. J. Exp. Med.163:632.
38.
LeJ.WeinsteinD.GublerU.VilcekJ., 1987. Induction of membrane-associated interleukin 1 by tumor necrosis factor in human fibroblasts. J. Immunol.138:2137.
39.
Solis-HerruzoJ.A.BrennerD.A.ChojkierM., 1988. Tumor necrosis factor α inhibits collagen gene transcription and collagen synthesis in cultured fibroblastsJ. Biol. Chem.263:5841.
40.
ManvielA.DaireauxM.RediniF.GaleraP.LoyauG.PujolJ.P., 1988. Tumor necrosis factor inhibits collagen and fibronectin synthesis in human dermal fibroblasts. FEBS Lett. 236:47.
41.
KahalehMB.SomaS.Y.LeRoyE.C., 1988. Effect of lymphotoxin and tumor necrosis factor on endothelial and connective tissue cell growth and function. Clin. Immunol. Immunopathol.49:261
42.
SchugerL.VaraniJ.MarkR.M.XunkelS.L.JohnonK.J.WardP.A., 1989. Cytotoxicity of tumor necrosis factor-α for human umbelical vein endothelial cells. Lab. Invest.61:62.
43.
TraceyK.J.WeiH.ManogueK.R.FongY.HesseD.G.NguyenN.T.KuoG.C.BeutlerB.CotranR.S.CeramiA.LowryS.F., 1988. Cachectin/tumor necrosis factor induces cachexia, anemia and inflammation. J. Exp. Med.167:1211.
