Regulation of innate immune response by MAP kinase phosphatase-1 - PubMed (original) (raw)

Review

Regulation of innate immune response by MAP kinase phosphatase-1

Xianxi Wang et al. Cell Signal. 2007 Jul.

Abstract

Mitogen-activated protein (MAP) kinase cascades are signal transduction pathways that play pivotal regulatory roles in the biosynthesis of pro-inflammatory cytokines. MAP kinase phosphatase (MKP)-1, an archetypal member of the MKP family, is essential for the dephosphorylation/deactivation of MAP kinases p38 and JNK. Earlier studies conducted using cultured immortalized macrophages provided compelling evidence indicating that MKP-1 deactivates p38 and JNK, thereby limiting pro-inflammatory cytokine biosynthesis in innate immune cells exposed to microbial components. Recent studies employing MKP-1 knockout mice have confirmed the central function of MKP-1 in the feedback control of p38 and JNK activity as well as the crucial physiological function of MKP-1 as a negative regulator of the synthesis of pro-inflammatory cytokines in vivo. MKP-1 was shown to be a major feedback regulator of the innate immune response and to play a critical role in preventing septic shock and multi-organ dysfunction during pathogenic infection. In this review, we will update the studies on the biochemical properties and the regulation of MKP-1, and summarize our understanding on the physiological function of this key phosphatase in the innate immune response.

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Figures

Figure 1. Diagram of the signal transduction pathways initiated at TLRs by microbial components

Binding of microbial components (ligands) to TLRs triggers conformational changes that lead to the recruitment of IRAK and TRAF-6 mediated by adaptor proteins MyD88 and TRIF. TRAF-6 can activate both the NFκB and MAP kinase pathways. NF-κB is critical for the transcription of inflammatory response genes, including genes of various cytokines and chemokines. MAP kinases, including ERK, JNK, and p38, also regulate the expression of many inflammatory genes. MAP kinases can activate AP-1 transcription factor, thus enhancing gene transcription. MAP kinases, p38 in particular, also enhance cytokine production through post-transcriptional mechanisms. p38 phosphorylates/activates MK-2, which in turn phosphorylates TTP, leading to both enhanced cytokine mRNA stability and accelerated cytokine mRNA translation.

Figure 2. Diagram of the structure and function of MKP-1

(A) Primary structure of MKP-1. MKP-1 has an amino terminal domain responsible for interaction with MAP kinases. The catalytic domain is located at the carboxyl terminus. (B) Feedback control of MAP kinases by MKP-1. Extracellular stimulation triggers the activation of MAP kinases. Upon activation, MAP kinases translocate to nucleus where they phosphorylate and activate transcription factors, leading to altered gene transcription. Among the genes activated by MAP kinases is MKP-1. MKP-1 protein can dephosphorylate MAP kinases, thus terminating MAP kinase-regulated gene transcription. By phosphorylating MKP-1 protein, MAP kinases can regulate the stability of MKP-1 protein.

Figure 3. Restraint of pro-inflammatory cytokine biosynthesis by MKP-1

In response to microbial infection, TLRs initiate a series of signal transduction pathways, including NF-κB and MAP kinase cascades, leading to production of pro-inflammatory cytokines. Simultaneously, the signals initiated at the TLRs also induce MKP-1 gene transcription. ERK regulates MKP-1 expression by two mechanisms: by enhanceing MKP-1 gene transcription and by phosphorylating MKP-1 and thereby increasing its half-life. The MKP-1 protein in turn dephosphorylates JNK and p38, thus stopping the perpetuation of the inflammatory cascades and terminating cytokine production.

Figure 4. Regulation of MKP-1 expression by immunomodulatory agents

Anti-inflammatory/immunosuppressive agents, such as glucocorticoids, IL-10, and glutamine, induce/augment MKP-1 expression, leading to inhibition of the p38 and JNK cascades and attenuation of inflammatory response. In contrast, pro-inflammatory cytokines, such as IFN-γ and MIF, inhibit MKP-1 expression, thereby perpetuating the p38 and JNK signalling pathways and enhancing the inflammatory response.

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Regulation of innate immune response by MAP kinase phosphatase-1 - PubMed (original) (raw)