RESUMO
The gastrointestinal tract can be involved in many autoimmune disorders, and women are affected more than men in most of the disease processes discussed. As this article outlines, gastrointestinal manifestations can be either part of the clinical presentation or complications of treatment. Depending on the disease process and the severity of symptoms, gastrointestinal evaluation and treatment can have an important role in the management of these diseases.
Assuntos
Doenças Autoimunes/complicações , Endoscopia Gastrointestinal , Gastroenteropatias/etiologia , Lúpus Eritematoso Sistêmico/complicações , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Artrite Reumatoide/complicações , Doenças Autoimunes/fisiopatologia , Síndrome de Behçet/complicações , Esofagite/complicações , Feminino , Motilidade Gastrointestinal , Granulomatose com Poliangiite/diagnóstico , Humanos , Masculino , Doença Mista do Tecido Conjuntivo/complicações , Esclerodermia Difusa/complicações , Esclerodermia Difusa/fisiopatologia , Fatores Sexuais , Síndrome de Sjogren/complicaçõesRESUMO
To attenuate injury during cholestasis, adaptive changes in bile acid transporter expression in the liver provide alternative bile acid excretory pathways. Apical sodium-dependent bile acid transporter (ASBT) (SLC10A2), only expressed in the liver on the cholangiocyte apical membrane, is rapidly regulated in response to inflammation and bile acids. Here, we studied the mechanisms controlling ASBT protein levels in cholangiocytes to determine whether ASBT expression is regulated by ubiquitination and disposal through the proteasome. Protein turnover assays demonstrated that ASBT is an unstable and short-lived protein. Treatment with MG-132, a proteasome inhibitor, causes time-dependent increased ASBT levels and increased intracellular accumulation of ASBT. In cells cotransfected with green fluorescent protein-tagged ASBT and hemagglutinin-tagged ubiquitin, we demonstrated coimmunoprecipitation and colocalization of ASBT and ubiquitin. Interleukin-1beta (IL-1beta) induced down-regulation of ASBT is abrogated by a JNK inhibitor and is accompanied by an increase in ASBT polyubiquitin conjugates and a reduced ASBT half-life. In phosphorylation-deficient S335A and T339A mutants, the ASBT half-life is markedly prolonged, IL-1beta-induced ASBT ubiquitination is significantly reduced, and IL-1beta fails to increase ASBT turnover. These results indicate that ASBT undergoes ubiquitin-proteasome degradation under basal conditions and that ASBT proteasome disposal is increased by IL-1beta due to JNK-regulated serine/threonine phosphorylation of ASBT protein at both Ser-335 and Thr-339. These studies are the first report of regulation of a bile acid transporter expression by the ubiquitin-proteasome pathway.
