Synergistic Induction of NR4A Orphan Nuclear Receptors by LPS and cAMP in Murine Macrophage Cells

Abstract

Although NR4A orphan nuclear receptors have been implicated in inflammatory gene expression and atherosclerosis, there is little information regarding their regulation by combinations of stimuli likely to be found in vivo, such as LPS and inducers of cAMP. LPS rapidly induced Nur77 and NOR1 mRNAs but had little effect on expression of Nurr1 mRNA. All three NR4Aswere rapidly induced by 8-bromo-cAMP and remained elevated for at least 8 h. Maximum induction of NOR1 by 8-bromo-cAMP was much greater than with LPS, but maximum induction of Nur77 was similar with both agents. Whereas Nurr1 mRNA had very little response to LPS, it was strongly induced by 8-bromo-cAMP, and Nurr1 mRNA levels remained elevated for at least 20 h. The combination of 8-bromo-cAMP and LPS acted synergistically to strongly induce NOR1 and Nur77, whereas LPS partially inhibited the induction of Nurr1 by 8-bromo-cAMP.Nurr1 protein levels correlated with Nurr1 mRNA levels but exhibited slower response kinetics.In summary, the NR4A receptors did not respond identically to individual stimuli or to combinations of stimuli. In particular, the magnitude of the responses to combinations of stimuli was quite different than to individual stimuli. Thus, NR4A receptor expression and the resulting functional consequences are more complex than appreciated from previous studies that evaluated regulation of NR4A expression by single stimuli. 2Nature Precedings :