Navegando por Palavras-chave "Via de sinalização JAK/STAT"

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    Avaliação do papel da proteína tirosina- kinase Janus kinase 2 (Jak-2) em modelo murino de lesão hepática induzida por isquemia e reperfusão
    (Universidade Federal de São Paulo (UNIFESP), 2010-05-26) Freitas, Maria Cecília de Santos [UNIFESP]; Pacheco-Silva, Alvaro [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    The Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling is one of the major pathways for cytokine signal transduction. However, the role of the JAK/STAT pathway in liver I/R is not clear. This study focuses on JAK2, which functions upstream of STAT-1 in JAK/STAT, and its role in the mechanism of liver IRI. Partial warm ischemia was produced in the hepatic lobes of C57BL/6 mice for 90min, followed by 6h of reperfusion. Mice were treated with JAK-2 inhibitor (Tyrphostin AG490; 40 mg/kg, i.p) or veicle, 60min prior to ischemic insult. JAK2 blockade resulted in significant reduction of hepatocyte apoptosis and liver injury. Macrophage and neutrophil infiltration, as assessed by immunohistochemistry, was markedly decreased in AG490-treated livers, compared with controls. The expression of proinflammatory cytokines (TNF-α, IL-6, IL-1β) and chemokines (CXCL-10 and CXCL-2) was also significantly reduced in AG490-treated group, compared with controls. AG490-treated livers showed less TUNEL positive cells and reduced cleaved caspase-3 protein expression in parallel with increased Bcl-XL expression. We employed AG490 (75 mM) in primary bone marrow-derived macrophage (BMM) and hepatoma cell (CRL1830) cultures, both stimulated with LPS (10 ng/ml). In BMM cultures, AG490 depressed otherwise LPSinduced pro-inflammatory gene expression programs (IL-6, IL-12b, IL-1β, CXCL-10 and iNOS). In hepatoma cells, AG490 reduced cleaved-caspase-3 expression. Moreover, JAK2 blockade inhibited STAT1 and STAT3 phosphorylation. This is the first report, which documents that JAK2 signaling is essential in the pathophysiology of liver IRI, as its selective blockage ameliorated the disease process and protected livers from inflammation and apoptosis.