MAPKAP Kinase 2-Deficient Mice Are Resistant to Collagen-Induced Arthritis

Abstract

TNF-α is a pleiotropic cytokine considered a primary mediator of immune regulation and inflammatory response and has been shown to play a central role in rheumatoid arthritis (RA). MAPKAP kinase 2 (MK2) is a serine/threonine kinase that is regulated through direct phosphorylation by p38 MAPK, and has been shown to be an essential component in the inflammatory response that regulates the biosynthesis of TNF-α at a posttranscriptional level. The murine model of collagen-induced arthritis (CIA) is an established disease model to study pathogenic mechanisms relevant to RA. In this study, we report that deletion of the MK2 gene in DBA/1LacJ mice confers protection against CIA. Interestingly, the MK2 heterozygous mutants display an intermediate level of protection when compared with homozygous mutant and wild-type littermates. We show that MK2−/− and MK2+/− mice exhibit decreased disease incidence and severity in the CIA disease model and reduced TNF-α and IL-6 serum levels following LPS/d-Gal treatment compared with wild-type mice. Additionally, we show that levels of IL-6 mRNA in paws of mice with CIA correlate with the disease status. These findings suggest that an MK2 inhibitor could be of great therapeutic value to treat inflammatory diseases like RA.

The α-Isoform of p38 MAPK Specifically Regulates Arthritic Bone Loss

“…Importantly, genetic deletion of MAPK kinase (MKK)3, an upstream activator of p38 MAPKs, or of MAPK-activated protein (MAPKAP)2, a downstream effector of p38 MAPKs, has shown to confer protection from arthritis (31,32). Thus, it is particularly important to understand the respective role of the various p38 MAPK isoforms on the course of inflammatory arthritis.…”

The Role of p38 MAPK in Rheumatic Diseases

“…Information on the involvement of MAPK signaling in the pathogenesis of PsA is very scarce, whereas activation of MAPKs, specifically p38 and downstream MK2, has been described in RA synovium and in the collagen-induced arthritis model of RA [64,75]. Recently, in a mouse model it has been shown that psoriatic skin inflammation facilitated the development of arthritis and enthesitis, both features of PsA [97].…”

“…These mice are deficient in the LPS-induced biosynthesis of several pro-inflammatory cytokines regulated by p38, including TNF-α, IFN-γ, IL-6, and IL-1. They survive LPS-induced endotoxic shock due to a reduction of the secretion of TNF-α by almost 90% [75]. MK2 has been considered as a key molecule participating in host defense against intracellular bacteria through regulation of both TNF-α and IFN-γ production [76,77].…”

MAP Kinase Cascades in Antigen Receptor Signaling and Physiology

“…p38α phosphorylates a variety of transcription factors, some of which are responsible for transcriptional expression of genes encoding inflammatory cytokines, as well as MAPKAP-K2 which is important for production of inflammatory cytokines, TNFα and IL-6, and progress of inflammatory disease (Hegen, Gaestel, Nickerson-Nutter, Lin, & Telliez, 2006). Indeed, ES cells taken from p38α-deficeint mice show a reduced capacity for IL-1-induced IL-6 production and activation of MAPKAP-K2 in response to chemical stress (Allen et al, 2000).…”