Transcription factors Elk-1 and SRF are engaged in IL1-dependent regulation of ZC3H12A expression

Here we report that the proinflammatory cytokine IL-1β rapidly induces the synthesis of MCPIP in primary monocyte-derived macrophages and HepG2 cells. This up-regulation takes place through the MAP kinase pathway and following activation of the transcription factor Elk-1. Using a ZC3H12A reporter construct we have shown that a ZC3H12A promoter region, stretching from -76 to +60, mediates activation by IL-1β. This region contains binding sites for Elk-1 and its partner SRF. Chromatin immunoprecipitation analysis confirms in vivo binding of both transcription factors to this region of the ZC3H12A promoter.We conclude that the transcription factor Elk-1 plays an important role in the activation of ZC3H12A expression in response to IL-1β stimulation.MCPIP has RNase activity that prevents some immune disorders by direct control of the stability of a set of inflammatory transcripts [1,2]. MCPIP-deficient mice die within 12 weeks with the symptoms of severe inflammatory changes. Among transcripts destabilized by MCPIP are the mRNAs for IL-6, IL-12p40, calcitonin receptorand and IL-1β [1,2]. MCPIP contains a PIN domain, responsible for it's enzymatic activity and CCCH zinc finger domain, partially also engaged in the control of transcripts decay [1,2]. MCPIP is induced in human peripherial blood monocytes by monocyte chemoattractant protein (MCP-1) and this phenomenon resulted in the name of this protein as a MCP-1 inducible protein (MCPIP) [3]. The significance of MCPIP in the course of inflammation is manifested also in the development of cardiovascular diseases. Elevated level of MCPIP is associated with ischemic heart disease [3]. Recently it was found that Toll-like receptors are involved in the activation of mice Zc3h12a (gene encoding MCPIP). The activation of Zc3h12a was revealed by microarray analysis of RNA from macrophages of wild-type, Myd88-/- and Trif-/-mice stimulated with liposacharide (LPS) [1]. We have observed that the level of transcript for MCPIP is rap