Mitogen-activated protein kinase phosphatase-1 (MKP-1): a critical regulator of innate immune responses

摘要

Innate immune responses mediated by macrophages and dendritic cells through Toll-like receptors (TLRs) play a central role in sensing and eliminating microbial pathogens. However, excessive innate immune responses can result in sepsis, autoimmunity, and chronic inflammation. Cells have evolved multiple mechanisms to prevent deleterious TLR activation, including transcriptional induction of intracellular negative regulators. Mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) is a nuclear-localized dual-specificity phosphatase that is induced by TLR stimulation in macrophages. MKP-1 preferentially dephosphorylates p38 MAPK and c-Jun N-terminal kinase, resulting in the attenuation of TLR-triggered production of pro-inflammatory cytokines and other inflammatory mediators. MKP-1 deficiency in mice leads to a markedly elevated susceptibility to endotoxic shock (a murine model of sepsis) and autoimmune arthritis, highlighting a key role for MKP-1 in regulating innate immunity. Herein we discuss biochemical activities and physiological functions of MKP-1 and the regulation of its expression in TLR-mediated innate immune responses.