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. Public Health Relevance: IL-17 is now recognized as an important regulator of inflammatory response. Because inflammation and cancer are believed to be causally related, it is important to understand how this process might be regulated to help prevent the initiation and development of this disease. Regulation of inflammation involves changes in the pattern of gene expression and this can be achieved through many molecular mechanisms. IL-17 appears to modulate the expression of chemokine genes that contribute in several ways to cancer development and spread and uses a mechanism that involves altering the rate at which the chemokine messenger RNA is degraded. This proposal is focused upon understanding the mechanisms through which IL-17 (and other stimuli) controls degradation of specific inflammation related messenger RNAs and thereby modulates aspects of inflammatory response.

Public Health Relevance

IL-17 is now recognized as an important regulator of inflammatory response. Because inflammation and cancer are believed to be causally related, it is important to understand how this process might be regulated to help prevent the initiation and development of this disease. Regulation of inflammation involves changes in the pattern of gene expression and this can be achieved through many molecular mechanisms. IL-17 appears to modulate the expression of chemokine genes that contribute in several ways to cancer development and spread and uses a mechanism that involves altering the rate at which the chemokine messenger RNA is degraded. This proposal is focused upon understanding the mechanisms through which IL-17 (and other stimuli) controls degradation of specific inflammation related messenger RNAs and thereby modulates aspects of inflammatory response.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA039621-29
Application #
8433260
Study Section
Special Emphasis Panel (ZRG1-IMM-C (02))
Program Officer
Howcroft, Thomas K
Project Start
1987-05-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
29
Fiscal Year
2013
Total Cost
$270,687
Indirect Cost
$98,275
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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Hartupee, Justin; Li, Xiaoxia; Hamilton, Thomas (2008) Interleukin 1alpha-induced NFkappaB activation and chemokine mRNA stabilization diverge at IRAK1. J Biol Chem 283:15689-93

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