REGULATION OF CCR2 CHEMOKINE RECEPTOR MESSENGER-RNA STABILITY

During inflammatory and immunological responses, leukocytes respond to external stimuli by altering the stability of cytokine and cytokine r eceptor messages, Change in message stability is an effective mechanis m for rapidly regulating steady state levels of mRNA. Cytokine message s containing A-U-rich elements located in the 3' untranslated region ( ARE) are the best studied examples of this process, AREs have been sho wn to act as targeting motifs for degradation of cytokine and transcri ption factor messages, We have recently observed that the interleukin- 8 (IL-8) receptor messages, IL-8RA and B (CXCR1 and CXCR2), also under go changes in stability in response to the inflammatory stimulator lip opolysaccharide (LPS), To determine whether regulation of message stab ility is a common mechanism for modulation of chemokine receptor mRNA we explored whether the stability of the CC chemokine receptor message for CCR2 (monocyte chemotactic protein-1 receptor) is also regulated by LPS. We found that LPS induces a rapid loss of steady state levels of CCR2 message through message degradation, Furthermore, LPS stimulat ed the decay of Poly(A) CCR2 mRNA faster than total CCR2 RNA, indicati ng that deadenylation is the first step in LPS-induced CCR2 RNA degrad ation, We conclude from these experiments that LPS stimulates the rapi d degradation of CCR2 messages through a two-step process, deadenylati on followed by degradation of the message body, In contrast to the res ults obtained for CCR2 nRNA, macrophage inflammatory protein-lot messa ges, which contain an ARE motif, were stabilized by LPS stimulation, i ndicating that chemokine and chemokine receptor mRNA stability are reg ulated by different and opposing mechanisms.