MAP kinase phosphatase-1, a gatekeeper of the acute innate immune response

Abstract

Mitogen-activated protein kinase (MAPK)§ cascades are crucial signaling pathways in the regulation of the host immune response to infection. MAPK phosphatase (MKP)-1, an archetypal member of the MKP family, plays a pivotal role in the down-regulation of p38 and JNK. Studies using cultured macrophages have demonstrated a pivotal role of MKP-1 in the restraint of the biosynthesis of both pro-inflammatory and anti-inflammatory cytokines as well as chemokines. Using MKP-1 knockout mice, several groups have not only confirmed the critical importance of MKP-1 in the regulation of the cytokine synthesis in vivo during the acute host response to bacterial infections, but also revealed novel functions of MKP-1 in maintaining bactericidal functions and host metabolic activities. RNA-seq analyses on livers of septic mice infected with E. coli have revealed that MKP-1 deficiency caused substantial perturbation in the expression of over 5000 genes, an impressive >20% of the entire murine genome. Among the genes whose expression are dramatically affected by MKP-1 deficiency are those encoding metabolic regulators and acute phase response proteins. These studies demonstrate that MKP-1 is an essential gate-keeper of the acute innate immune response, facilitating pathogen killing and regulating the metabolic response during pathogenic infection. In this review article, we will summarize the studies on the function of MKP-1 during acute innate immune response in the regulation of inflammation, metabolism, and acute phase response. We will also discuss the role of MKP-1 in the actions of numerous immunomodulatory agents.