Post-transcriptional control of inflammatory gene expression

Cleveland Clinic Lerner Com-Cwru, Cleveland OH

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Abstract

DESCRIPTION (provided by applicant): Inflammation is now recognized as an important feature governing the development and spread of cancer. Hence understanding and controlling the inflammatory process is an important target both for prevention and control of malignancy. IL-17 is now recognized as an important regulator of inflammation in part via the induction of chemokine gene expression using a mechanism that depends upon the control of mRNA half-life. Rapid mRNA decay helps diminish inappropriate expression of pro-inflammatory gene products and IL-17 can markedly enhance expression by prolonging half-lives. This behavior is largely a result of regulatory sequences located within the primary sequence of mature target mRNAs. One well documented pathway regulating chemokine mRNA decay involves AUUUA-containing AU rich sequence elements (AREs) that are recognized by the ARE binding protein Tristetraprolin (TTP). This process of rapid mRNA decay is controlled via Toll/Interleukin-1 Receptor (TIR) stimulation of the p38 MAP kinase signaling cascade. While the mouse CXC chemokine KC (CXCL1) can be a target for the action of the AUUUA/TTP/p38 pathway in LPS- stimulated macrophages, we have shown that IL-17 stabilizes TNF-induced KC mRNA in non-myeloid cell populations and signals through the adaptor protein Act 1. Our preliminary findings support the hypothesis that IL-17 (and IL-1 under some conditions) utilizes a second mechanistic pathway to achieve stabilization of KC mRNA. This pathway can be distinguished from the AUUUA/TTP/p38-dependent mechanism by multiple criteria including specific nucleotide sequence requirements, RNA-binding protein participation, and receptor-coupled signaling events. This hypothesis will be tested by (1) identification of the sequence motifs that define the AUUUA/TTP-independent mRNA instability and sensitivity for stabilization by IL-17, (2) identification of RNA binding molecules responsible for TTP- independent mRNA instability and characterization of their ability to promote IL-17-induced mRNA stabilization, and (3) identification and definition of the signaling events coupling IL-17R and IL-1R stimulation with p38/MK2- independent mRNA stabilization.