Analise dos efeitos e dos mecanismos de ação do fator de crescimento transformante- beta 1, interferon gama e iclosporina A na transdiferenciação dos fibroblastos gengivais em miofibroblastos / Effects of transforming growth factor- beta 1, interferon gamma and cyclosporin A on transdifferentiation of gingival fibroblasts in myofibroblasts

AUTOR(ES)

Lays Martin Sobral

DATA DE PUBLICAÇÃO

2007

RESUMO

Myofibroblasts are the main cellular type involved in extracellular matrix deposition in fibrotic diseases. Relatively little is known about the underlying mechanisms that regulate myofibroblast emergence (transdifferentiation), however the regulatory cytokine transforming growth factor-beta 1 (TGF- beta 1) has been traditionally considered an inducer of the myofibroblastic phenotype via activation of connective tissue growth factor (CTGF)-dependent pathway. Some inflammatory cytokines, particularly interferon g (IFN gama ), show opposite effects to TGF- beta 1, inhibiting myofibroblast transdifferentiation. Cyclosporin A (CsA) is a widely used immunosuppressant drug that causes significant side effects such as gingival overgrowth. Normal gingival fibroblast cell lines treated with CsA express high levels of TGF- beta 1 and collagen, which are intrinsic of myofibroblasts. In the present study we examined whether TGF- beta 1 and IFN gama can modulate transdifferentiation of gingival fibroblasts into myofibroblasts, and the biologic mechanisms behind those factors in this process. Additionally, we have analyzed the presence of myofibroblasts in CsA-induced gingival overgrowth. Our results demonstrated throughout a modality of experiments that included reverse trancriptasepolymerase chain reaction (RT-PCR), western blot, immunofluorescence and flow citometry analysis, that TGF- beta 1 induces and IFN gama blocks fibroblast-myofibroblast transdifferentiation in a dose- and time-dependent manner. In fibroblasts with CTGF levels know-down by specific small interference RNA, TGF- beta 1 effect on transdifferentiation was significantly reduced, revealing that CTGF plays a crucial role in mediating TGF- beta 1 myofibroblast transdifferentiation. IFN gama blocked myofibroblast transdifferentiation by stimulating Smad 7 levels, a protein that negatively regulates TGF- beta 1 signaling. Interestingly, myofibroblasts were not found in CsA-induced gingival overgrowth, as revealed by the in vivo model of daily injections of CsA in Wistar rats and by the in vitro model of gingival fibroblast cultures treated with CsA. Although CsA treatment stimulated TGF- beta 1 expression by NG fibroblasts, it lacked to induce CTGF levels. Our results demonstrate that TGF- beta 1 induction of transdifferentiation of gingival fibroblasts to myofibroblasts occurs via a CTGF dependent pathway. Additionally, this study suggests that IFN gama may be clinically effective in the treatment of fibrotic diseases associate with myofibroblast

ASSUNTO(S)

fibromatose gengival gingival fibromatosis interferon-gama transforming growth factor beta fibroblasts fator de crescimeto transformante-beta1 fibroblastos interferongamma

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