MAPK phosphatases — regulating the immune response

Abstract

Mitogen-activated protein kinase (MAPK) phosphatases (MKPs) are protein phosphatases that dephosphorylate both the phosphothreonine and phosphotyrosine residues on activated MAPKs. Removal of the phosphates renders MAPKs inactive, effectively halting their cellular function. In recent years, evidence has emerged that, similar to MAPKs, MKPs are pivotal in the regulation of immune responses. By deactivating MAPKs, MKPs can modulate both innate and adaptive immunity. A number of immunomodulatory agents have been found to influence the expression of MKP1 in particular, highlighting the central role of this phosphatase in immune regulation. This Review discusses the properties, function and regulation of MKPs during immune responses.

Anti-inflammatory functions of glucocorticoid-induced genes

“…Dual specificity phosphatase 1 (DUSP1) is the first described member of a large family of phosphatases that catalyse removal of phosphate from serine, threonine or tyrosine residues (Dickinson and Keyse, 2006;Liu et al, 2007;Theodosiou and Ashworth, 2002). It is expressed in response to GCs A Clark Anti-inflammatory functions of glucocorticoid-induced genes Page 18 of 53 in a wide variety of cell types including mast cells (Kassel et al, 2001), monocytes or macrophages (Abraham et al, 2006;Aeberli et al, 2006;Bhattacharyya et al, 2007;Chen et al, 2002;Zhao et al, 2005), microglia (Zhou et al, 2007), T lymphocytes , dermal, lung and synovial fibroblasts (Phillips et al, 2006;Toh et al, 2004;Yang et al, 2006), endothelial cells (Furst et al, 2007), osteoblasts (Engelbrecht et al, 2003;Leclerc et al, 2004), keratinocytes (Onda et al, 2006;Stojadinovic et al, 2006), adipocytes (Bazuine et al, 2004), lung epithelial cells (Chivers et al, 2006;Hermoso et al, 2004), airway smooth muscle cells (Issa et al, 2007) and HeLa cells (Imasato et al, 2002;Lasa et al, 2002).…”

“…In LPS-induced endotoxemia and collagen-induced arthritis (experimental models of acute or chronic inflammation, respectively), DUSP1 -/-mice show exaggerated responses (Chi et al, 2006;Hammer et al, 2006;Salojin et al, 2006;Zhao et al, 2006). Hence DUSP1 is an important negative regulator of inflammatory responses (Abraham and Clark, 2006;Dickinson and Keyse, 2006;Lang et al, 2006;Liu et al, 2007), and its induction by GCs is potentially a powerful anti-inflammatory mechanism (Clark, 2003;Clark and Lasa, 2003). Indeed, a variety of commonly prescribed GCs induced DUSP1 expression in alveolar macrophages in a manner roughly proportional to their anti-inflammatory efficacies .…”

Dual-Specificity Phosphatase 14 (DUSP14/MKP6) Negatively Regulates TCR Signaling by Inhibiting TAB1 Activation

“…The biological outcome of MAPK signaling is dictated by the duration and magnitude of kinase activation. Dual-specificity phosphatases (DUSPs) are responsible for dephosphorylating both threonine and tyrosine residues within the Thr-X-Tyr motif in MAPKs (3). DUSPs can be categorized into typical DUSPs (also known as MAPK phosphatases [MKPs]), which contain an N-terminal region composed of two CDC25 homology 2 (CH2) domains and a C-terminal catalytic domain, and atypical DUSPs, which lack the N-terminal CH2 domain (4).…”

Compound FLZ inhibits lipopolysaccharide-induced inflammatory effects via down-regulation of the TAK-IKK and TAK-JNK/p38MAPK pathways in RAW264.7 macrophages

“…The nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways are the most important networks for the regulation of many genes involved in inflammatory response [14,15] . NF-κB exists mainly as a heterodimer composed of subunits of the Rel family, p50 and p65.…”

“…NF-κB is then released and translocates to the nucleus, where it triggers the transcription of multiple genes through the cis-acting κB element. The MAPKs are a family of serine/ threonine protein kinases, including c-Jun NH 2 -terminal kinase ( JNK) and p38 MAPK, that play important roles in inflammatory responses [15] . Transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) was first identified as a kinase involved in TGF-β signaling and was later shown to be a pivotal factor for MAPK and NF-κB activation in response to TLR, IL-1R and TNFR stimulation [16] .…”