Effect of Tyrosine Kinase Inhibitor AG-490 on the Development of Aseptic Shock

Abstract

ABSTRACTRecently, protein kinase inhibitors are used to limit the uncontrolled immune responses in cancer and autoimmune diseases. Tyrphostin AG-490 is a novel benzylidine malononitrile analogue that inhibits the activity of Janus activation kinase 2 (JAK2). In the present study we investigate the effect of the drug on the development of aseptic shock. The acute inflammation was provoked in mice with severe combined immunodeficiency (SCID) by intraperitoneal injection of 0.8 mg/g body weight of zymosan. Tyrphostin AG-490 was administrated intraperitoneally in a dose of 5 mg/kg. Blood, liver and spleens were collected on day 21 of shock. The white blood cell differential count showed that the percentage of polymorphonuclear cells in peripheral blood was not affected by AG-490 administration. The proportion of blood monocytes increased 2 times in shock mice and returned to the baseline value in AG-490-treated mice. At the late phase of zymosan-induced inflammation SCID mice had enlarged spleens and increased numbers of splenocytes that were significantly reduced by AG-490 administration. Interestingly, the elevated number of hepatocytes and the enhanced ability of hepatocytes to produce nitric oxide (NO) in response to zymosan restimulation in vitro were observed in the group of AG-490-treated mice with shock. These data suggest that the inhibition of JAK2 kinase can stimulate the NO inflammatory pathway in liver when functional T and B cells are missing. Our study has performed an evidence for the decisive role of T and B cells for the resolution of inflammation and cell repair in the liver.