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Interleukin-10 (IL-10) mediates an anti-inflammatory response that is executed through the expression of IL-10-induced genes. Certain IL-10-induced genes, exemplified by TNIP3, are induced by IL-10 only in conjunction with a pro-inflammatory signal. We sought to characterize the mechanism whereby IL-10 and Toll-like receptor signals synergized to induce expression of genes like TNIP3 inmacrophages. Stimulation with IL-10 and lipopolysaccharide (LPS) synergistically induced an increase in the transcription rate of TNIP3, while having no effect on its mRNA stability. This transcriptional mechanism proved to be generalizable to 14 other genes that also were synergistically induced by IL-10 and LPS in monocytes/macrophages. Although all of the genes had this synergistic transcriptional regulation in common, they could be divided into three subsets based on their differential requirements for de novo protein synthesis and kinetics of expression: namely, primary response genes, early secondary response genes, and late secondary response genes. This coordinated and temporal pattern of transcriptional regulation in response to IL-10 and LPS was conserved in both human and mouse monocytes/macrophages, and it was associated with differential dependencies on PI3K and JNK signaling pathways. These results underscore the complex nature of the IL-10-induced transcriptional response that occurs specifically in LPS-triggered macrophages.