The role of cytokine mRNA stability in the pathogenesis of autoimmune disease.
Inflammatory cytokines such as interferon (IFN)-gamma, interleukin (IL)-2, tumor-necrosis factor (TNF)-alpha and IL-17 play an important role in the pathogenesis of cell-mediated autoimmune diseases. Cytokine gene expression is tightly regulated at the post-transcriptional level. Cytokine mRNA decay is dependent not only upon cis-elements in the RNA but also upon trans-acting factors such as the RNA binding proteins TTP, HuR, AUF-1, Nucleolin and YB-1. Physiologic signals, for instance signaling through the CD28 receptor on T cells, can modulate the half-life of a select subset of cytokine mRNAs, such as IL-2. Distinct cis- and trans-acting elements in human and mouse IL-2 mRNA may account for the different pattern of CD28-mediated mRNA stabilization in these two species. TTP-deficient mice or mice with a deletion of the TNF-alpha mRNA ARE element develop a complex inflammatory syndrome that is associated with a prolonged TNF-alpha mRNA half-life and elevated levels of circulating TNF-alpha. This syndrome can be prevented by treatment with TNF-alpha blocking antibodies. Evidence from mice with altered cytokine mRNA stability, along with human data, suggests that imbalance between the stability and decay of inflammatory cytokine mRNAs could represent a basic mechanism leading to autoimmunity.
Seko
Yuko
Y
Laboratory of Immunology, The National Eye Institute, The National Institutes of Health, Bldg. 10, Rm. 10N112, 10 Center Dr. MSC-1857, Bethesda, MD 20892, USA.
Cole
Steven
S
Kasprzak
Wojciech
W
Shapiro
Bruce A
BA
Ragheb
Jack A
JA
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology; D016207:Cytokines / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology; D051379:Mice; D020871:RNA Stability / Q000235:genetics* / Q000276:immunology
D016207:Cytokines; D007376:Interleukin-2