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Keywords:

  • Inflammation;
  • Cytokines;
  • Signal transduction;
  • Macrophages;
  • Protein kinases

Summary

Great effort has been paid to identify novel targets for pharmaceutical intervention to control inflammation associated with different diseases. We have studied the effect of signaling inhibitors in the secretion of the proinflammatory and profibrogenic cytokine IL-1β in monocyte-derived macrophages (M-DM) obtained from the ascites of cirrhotic patients and compared with those obtained from the blood of healthy donors. Peritoneal M-DM were isolated from non-infected ascites of cirrhotic patients and stimulated in vitro with LPS and heat killed Candida albicans in the presence or absence of inhibitors for JNK, MEK1, p38 MAPK and PI3K. The IL1B and CASP1 gene expression were evaluated by qRT-PCR. The expression of IL-1β and caspase-1 were determined by Western Blot. IL-1β was also assayed by ELISA in cell culture supernatants. Results revealed that MEK1 and JNK inhibition significantly reduced the basal and stimulated IL-1β secretion, while the p38 MAPK inhibitor had no effect on IL-1β levels. On the contrary, inhibition of PI3K increased the secretion of IL-1β from stimulated M-DM. The activating effect of PI3K inhibitor on IL-1β release was mainly mediated by the enhancement of the intracellular IL-1β and caspase-1 content release to the extracellular medium and not by increasing the corresponding mRNA and protein expression levels. These data point towards the role of MEK1 and JNK inhibitors, in contrast to the PI3K-Akt ones, as potential therapeutic tools for pharmaceutical intervention to diminish hepatic damage by reducing the inflammatory response mediated by IL-1β associated to liver failure.