Fig. 2.

Restraint of pro-inflammatory cytokine biosynthesis by MKP-1. (A). Diagram illustrating the role of MKP-1 in the regulation of the innate immune response. In response to microbial infection, TLRs engage various adaptor proteins, including MyD88, TRAM, TRIF, via the Toll/IL-1 receptor (TIR) homology domains. While MyD88 can activate TRAF6 through IL-1 receptor-associated kinases (IRAKs), TRIF can also activate TRAF6 through a mechanism independent of IRAKs. TRAF6 can turn on both the IKK/NF-κB and MAPK pathways. IKKs will phosphorylate IκB leading to its degradation and resulting translocation of NF-κB transcription factor to the nucleus. MAPKs can also phosphorylate certain transcription factors to modulate their activities. In the nucleus, NF-κB regulate the transcription of cytokine genes, sometimes in cooperation with transcription factors controlled by MAPKs. p38 phosphorylates/activates MK-2, which in turn phosphorylates TTP, leading to both enhanced cytokine mRNA stability and accelerated cytokine mRNA translation, ultimately resulting in enhanced cytokine production. Simultaneously, activation of TLRs also induce MKP-1 gene transcription through a signaling process, at least partially mediated by ERK, leading to the production of MKP-1 protein. ERK also increases MKP-1 protein stability via phosphorylating MKP-1, leading to a rapid accumulation of MKP-1 protein. The MKP-1 protein in turn dephosphorylates MAPKs, particularly JNK and p38, thus stopping the perpetuation of the inflammatory cascades and terminating cytokine production. DD, death domain. (B) Dynamic shifting of the inflammatory signaling events as well as cytokine synthesis and levels at different phases after microbial infection.