Regulation pattern of fish irf4 (the gene encoding IFN regulatory factor 4) by STAT6, c-Rel and IRF4

Interferon regulatory factor 4 (IRF4) plays pivotal roles in both innate and adaptive immune responses in mammals. In fish, there are two homologues of irf4, irf4a and irf4b. In this study, we examined the regulatory patterns of zebrafish irf4a and irf4b by STAT6 and c-Rel. Firstly, expression of irf4a and irf4b was monitored in several tissues at mRNA level. By infection with SVCV, irf4a and irf4b were upregulated in both kidney and spleen, and were immediately induced by treatment with poly I:C in ZF4 cells. Moreover, the activation of irf4a promoter was regulated by overexpression of stat6 and c-rel in a cooperation manner, which could be inhibited by mutation of the putative binding sites of STAT6 and c-Rel in irf4a promoter region. However, irf4b promoter was activated slightly only by STAT6 but not c-Rel. Furthermore, overexpression of irf4a inhibited the activation of its own promoter under induction of STAT6 and c-Rel, which was the result of that IRF4a bound to STAT6 and c-Rel directly. In addition, cellular location analysis showed that IRF4a was located only in nuclear region. These data indicate that fish irf4a can also be upregulated by STAT6 and c-Rel.