Chemokine and chemoattractant receptor expression: post-transcriptional regulation

The magnitude and character of the inflammatory process are determined in part via the trafficking of leukocytes into sites of injury and infection, and this process depends on proper control of the expression of genes encoding chemoattractant peptides and their receptors. Although these controls operate at multiple mechanistic levels, recent evidence indicates that post-transcriptional events governing the half-life of select mRNAs are important determinants. Adenine-uridine rich elements (AREs) located within 3' untranslated regions (UTRs) confer constitutive mRNA instability and in some cases, stabilization following stimulation by ligands of the Toll-IL-1 receptor (TIR) family. Although the importance of AREs in determining activity and mRNA half-life is well-recognized, the mechanistic scope and diversity remain poorly understood. Using the mouse KC or CXCL1 gene as a model, we have demonstrated that the abundance of mRNA and protein produced during an inflammatory response depends on multiple mechanistically distinct AREs present in the 3' UTR of the mRNA. The mRNA encoding the receptor for N-terminal formyl-methionine-containing peptides is also unstable and subject to stabilization in response to TIR ligands. These two models can, however, be readily distinguished from one another on the basis of specific stimulus sensitivity and the signaling pathways, through which such stimuli couple to the control of mRNA decay. These models demonstrate the substantial diversity operative in the post-transcriptional regulation of inflammatory gene expression.