RESUMEN
Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease caused by intrahepatic bile duct injuries, resulting in fibrosis, cirrhosis, and eventually liver failure. T helper (Th) 17 cells are proposed to involve in the pathogenesis of PBC. However, how and which Th17 cell-derived cytokines affect PBC remains unclear. In this study, we investigated the effects of Th17 effector cytokines, including interleukin (IL)-17A, IL-17F, and IL-21 in PBC using a xenobiotic-induced mouse model of autoimmune cholangitis (inducible chemical xenobiotic models of PBC) treated with cytokine-expressing adeno-associated virus. Our results showed that administration of IL-17A, the well-known main cytokine produced by Th17 cells, did not augment liver inflammation or fibrosis. In contrast, we noted IL-17A-treated mice had lower hepatic Th1 cell numbers and higher hepatic CD11b+Ly6G+ polymorphonuclear myeloid-derived suppressor cell numbers. IL-17F did not alter liver inflammation or fibrosis. However, the administration of IL-21 exacerbated liver inflammatory responses and portal cell infiltration. IL-21 markedly increased the numbers of activated CD8+ T cells and liver tissue-resident memory CD8+ T cells. Moreover, IL-21 aggravates liver fibrosis in mice with autoimmune cholangitis. These results emphasized that not IL-17A but IL-21 in Th17 cell-derived cytokines affected the pathogenesis of PBC. IL-21 enhanced liver inflammation and progression to fibrosis by enhancing the numbers and effector activities of CD8+ T cells. Delineation of the effects of different Th17 effector cytokines in PBC offers clues for developing new therapeutic approaches.
Asunto(s)
Enfermedades Autoinmunes , Colangitis , Cirrosis Hepática Biliar , Animales , Ratones , Interleucina-17 , Xenobióticos , Interleucinas , Citocinas , Colangitis/patología , Fibrosis , Cirrosis Hepática , Enfermedades Autoinmunes/patología , InflamaciónRESUMEN
Using flow cytometry analysis, the flagellin of Burkholderia pseudomallei acts as a signalling inducer, and evokes an increase in the intracellular calcium ion concentration ([Ca(2+)]i) in human peripheral blood mononuclear cells (PBMC). The cells with increased [Ca(2+)]i segregate into the live monocyte gate and not into the live lymphocyte gates. The stimulated [Ca(2+)]i increase can be neutralized with anti-flagellin antibodies. In the absence of [Ca(2+)], [Ca(2+)]i was increased rapidly in flagellin-treated cells compared to non-flagellin-treated cells only after the addition of 1 mM CaCl(2). Selective calcium antagonists were used to effectively block the [Ca(2+)]i signal, revealing that this signal was decreased by the addition of L-type calcium channel blockers (diltiazem, nifedipine and verapamil) and La(2+) but was not changed by the addition of a T-type calcium channel blocker (flunarizine). It seemed that flagellin facilitates [Ca(2+)]i influx via a La(2+) sensitive L-type cellular membrane channel. Furthermore, flagellin also acts as a TNF-alpha inducer in a time- and concentration-dependent manner when adhered mononuclear cells are treated with flagellin. This ability to induce TNF-alpha production was affected by the presence of [Ca(2+)] in the culture medium. It suggested that B. pseudomallei flagellin is an immuno-stimulatory molecule, causing an increase in [Ca(2+)]i and an up-regulation of TNF-alpha, which may play an important role in the inflammation process.