Role of PI3K and MAPK in Regulating the IL-10-Induced Temporal Transcriptional Program in LPS-Triggered Macrophages
To mitigate damage to host tissues associated with a prolonged inflammatory state, the cytokine interleukin-10 (IL-10) induces expression of a set of anti-inflammatory genes that act to inhibit expression of TLR-induced pro-inflammatory genes. While many of the IL-10-induced genes can be induced by IL-10 stimulation alone, some others, such as TNIP3, are only IL-10-inducible in the presence of concurrent TLR signaling, and are thus termed IL-10 super-induced genes. TNIP3 is part of a larger cohort of IL-10 super-induced genes, and the synergy for these genes occurs at a transcriptional level, not due to mRNA stabilization. Furthermore, these IL-10 super-induced genes can be subdivided into three distinct kinetic profiles: primary response genes, early-induced secondary response genes, and late-induced secondary response genes. To further understand the regulatory mechanisms in play, I used ChIP and reporter gene assays to confirm the IL-10 super-induction of these genes occurs at the level of transcription, depending on an increase of RNA polymerase II recruitment to the TNIP3 promoter. Additionally, I found that the three-wave kinetic profiles of induction are conserved in both human and mouse macrophages, and that the coordinated and temporal expression of the three gene subsets appears to correlate with differing dependencies on PI3K and JNK signaling pathways.
IL-10, toll-like receptor, macrophages, transcriptional control, TNIP3, PI3K, MAPK, Biology
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