CREB and AP‐1 activation regulates MKP‐1 induction by LPS or M‐CSF and their kinetics correlate with macrophage activation versus proliferation

MAPK phosphatase‐1 (MKP‐1) is a protein phosphatase that plays a crucial role in innate immunity. This phosphatase inactivates ERK1/2, which are involved in two opposite functional activities of the macrophage, namely proliferation and activation. Here we found that although macrophage proliferation and activation induce MKP‐1 with different kinetics, gene expression is mediated by the proximal promoter sequences localized between ?380 and ?180 bp. Mutagenesis experiments of the proximal element determined that CRE/AP‐1 is required for LPS‐ or M‐CSF‐induced activation of the MKP‐1 gene. Moreover, the results from gel shift analysis and chromatin immunoprecipitation indicated that c‐Jun and CREB bind to the CRE/AP‐1 box. The distinct kinetics shown by M‐CSF and LPS correlates with the induction of JNK and c‐jun, as well as the requirement for Raf‐1. The signal transduction pathways that activate the induction of MKP‐1 correlate kinetically with induction by M‐CSF and LPS.