TGF-β induces IL-15 in hepatocytes. Is it then opposing TGFβ in a negative feedback manner? Does this mechanism play a role in liver disease?

Liver fibrogenesis is a process involving the participation of several cellular components. We described a new role for hepatocytes in the process of fibrogenesis, in which TGFbeta induces expression and secretion of CTGF, another potent profibrogenic cytokine. Recently Interleukin-15 has emerged as a new player in several models of liver damage, but its precise role has not yet been determined. Real Time PCR showed that TGFbeta induces IL-15 mRNA up to 80 fold after 24h in primary hepatocytes, and up to 10 fold in AML12 cells. Using chemical inhibitors we determined that although ALK5 activity is essential, ERK and JNK pathways cooperate in this induction. Two isoforms are expressed, differing in the length of the signal peptide. By PCR we observed induction of both splice variants of IL-15. Using siRNA we determined that Smad3 but not Smad2 is partially necessary for IL-15 mRNA induction. Software analysis of a -1,8kb region of mouse IL-15 promoter revealed binding sites for Smad3, Fast-1 and AP-1 highlighting the potential cooperation between Smad3 and AP-1 complexes. By ELISA we detected IL-15 in cell pellets but not in supernatants, indicating that IL-15 and IL-15/IL-15R complex are not secreted. Immunohistochemistry analysis of mouse and human livers revealed expression of IL-15 in hepatocytes found increased in TGFbeta transgenic mice, and in patients with liver fibrosis due to HBV, Schistosoma japonicum and gallstone bladder. Our results indicate that a new potent cytokine is induced in hepatocytes by TGFbeta. We are currently investigating the biological significance of this finding with regard to TGFbeta induced hepatocyte apoptosis, EMT and fibrotic processes.

Liver disease - Liver fibrosis - TGFbeta - il-15