NIH Research Festival
C-reactive protein (CRP), an acute phase plasma protein, is a major component of inflammatory reactions functioning as a mediator of innate immunity. It has been widely used as a validated clinical biomarker of the inflammatory state in trauma, infection, and age associated chronic diseases including cancer and cardiovascular disease (CVD). Despite several active therapeutic trials of agents that reduce serum CRP by inhibiting the IL-6 signaling pathway, the molecular mechanisms that regulate CRP expression are not well understood. Given that the CRP 3’-untranslated region (UTR) is long and AU-rich, we hypothesized that CRP may be regulated post-transcriptionally by RNA-binding proteins (RBP) and by microRNAs (miRNA). Here, we show that CRP expression is regulated post-transcriptionally via factors that associate with the CRP 3’UTR. The RBP HuR binds directly to the CRP 3’UTR and affects CRP mRNA levels. Through this interaction, HuR selectively increases CRP mRNA stability and promotes CRP translation. Interestingly, treatment with the age-associated inflammatory cytokine IL-6 increases binding of HuR to CRP mRNA, and conversely, HuR is required for IL-6 mediated up-regulation of CRP. In addition, we identify miR-637 as a miRNA that potently inhibited CRP expression in competition with HuR. Taken together, we have uncovered an important post-transcriptional mechanism that modulates expression of the inflammatory marker CRP, which may be utilized in the development of treatments for inflammatory processes that cause CVD and age-related diseases.
Scientific Focus Area: Molecular Biology and Biochemistry
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