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In human monocyte-derived macrophages, the MCPIP gene (monocyte chemoattractant protein-induced protein) is strongly activated by interleukin-1β (IL-1β). Using bioinformatics, a PIN domain was identified, spanning amino acids 130-280; such domains are known to possess structural features of RNases. Recently, RNase properties of MCPIP were confirmed on transcripts coding for interleukins IL-6 and IL-12p40. Here we present evidence that siRNA-mediated inhibition of the MCPIP gene expression increases the level of the IL-1β transcript in cells stimulated with LPS, whereas overexpression of MCPIP exerts opposite effects. Cells with an increased level of wild-type MCPIP showed lower levels of IL-1β mRNA. However, this was not observed when mutant forms of MCPIP, either entirely lacking the PIN domain or with point mutations in this domain, were used. The results of experiments with actinomycin D indicate that lower levels of IL-1β mRNA are due to shortening of the IL-1β transcript half-life, and are not related to the presence of AU-rich elements in the 3′ UTR. The interaction of the MCPIP with transcripts of both IL-1β and MCPIP observed in an RNA immunoprecipitation assay suggests that this novel RNase may be involved in the regulation of expression of several genes.