The identification of C/EBPβ as a transcription factor necessary for the induction of MAPK phosphatase-1 by toll-like receptor-4 ligand

Toll-like receptor activates mitogen-activated protein kinases (MAPKs), which contributes to inflammatory responses. The activities of MAPKs are counter-balanced by MAPK phosphatases (MKPs). Because the transcriptional regulatory mechanism of mkp-1 has not been completely established, this study investigated the effect of toll-like receptor-4 ligand (TLR4L, lipopolysaccharide) on CCAAT/enhancer binding protein-β (C/EBPβ)-dependent induction of MKP-1 in Raw264.7 cells. TLR4L treatment induced MKP-1 through gene transcription. Other TLRLs also transactivated mkp-1. Gel-shift, immunoblot and chromatin immunoprecipitation assays identified the activation of C/EBPβ by TLR4L. Consistently, C/EBPβ transfection promoted mkp-1 transactivation, which was reversed by its dominant-negative mutant (AC/EBP). Experiments using chemical inhibitors or dominant-negative mutants of MAPKs indicated that both C/EBPβ activation and MKP-1 induction depend on the activation of MAPKs. TLR4L activation of C/EBPβ also contributed to the induction of dusp-2, dusp-4, dusp-8 and dusp-16. These results identify C/EBPβ as a transcription factor necessary for the induction of MKP-1 by TLRL.