DUSP Meet Immunology: Dual Specificity MAPK Phosphatases in Control of the Inflammatory Response

Abstract

The MAPK family members p38, JNK, and ERK are all activated downstream of innate immunity’s TLR to induce the production of cytokines and inflammatory mediators. However, the relative intensity and duration of the activation of different MAPK appears to determine the type of immune response. The mammalian genome encodes a large number of dual specificity phosphatases (DUSP), many of which act as MAPK phosphatases. In this study, we review the emergence of several DUSP as genes that are differentially expressed and regulated in immune cells. Recently, a series of investigations in mice deficient in DUSP1, DUSP2, or DUSP10 revealed specificity in the regulation of the different MAPK proteins, and defined essential roles in models of local and systemic inflammation. The DUSP family is proposed as a set of molecular control devices specifying and modulating MAPK signaling, which may be targeted to unleash or attenuate innate and adaptive immune effector functions.

CpG- and LPS-activated MAPK signaling in in vitro cultured salmon (Salmo salar) mononuclear phagocytes

“…It has for a long time been known that p38 activates a negative feedback loop which in addition to p38 also affects ERK and JNK activity [20]. Upregulation of various phosphatases such as dual specificity phosphatases (DUSP) is an important mechanism through which MAPK activity is controlled [21], [22]. In the current study the CpG-and LPS-induced upregulation of DUSP5, a molecule which in mammals specifically dephosphorylates ERK, appeared to be completely p38-dependent as indicated by the microarray analysis and may have been involved in negative regulation of ERK activity by p38.…”

MAPK signaling in inflammation-associated cancer development

“…DUSPs inactivate MAPK signaling by removing the phosphate group from the threonine and tyrosine residues. Recent studies in mice deficient in DUSP1, DUSP2 or DUSP10 has defined essential roles of DUSPs in local and systemic inflammation (Lang et al, 2006). For example, DUSP1 has been found to dephosphorylate p38 MAPK in activated macrophages, leading to reduced production of TNFα, IL-6 and IL-10 upon stimulation with TLR-ligands (Lang et al, 2006).…”

“…Recent studies in mice deficient in DUSP1, DUSP2 or DUSP10 has defined essential roles of DUSPs in local and systemic inflammation (Lang et al, 2006). For example, DUSP1 has been found to dephosphorylate p38 MAPK in activated macrophages, leading to reduced production of TNFα, IL-6 and IL-10 upon stimulation with TLR-ligands (Lang et al, 2006). In addition, DUSP1-deficient mice show high susceptibility to LPSinduced septic shock and collagen-induced arthritis (Lang et al, 2006).…”

“…For example, DUSP1 has been found to dephosphorylate p38 MAPK in activated macrophages, leading to reduced production of TNFα, IL-6 and IL-10 upon stimulation with TLR-ligands (Lang et al, 2006). In addition, DUSP1-deficient mice show high susceptibility to LPSinduced septic shock and collagen-induced arthritis (Lang et al, 2006). Interestingly, DUSP2-deficient macrophages produce attenuated levels of inflammatory mediators, probably due to a negative feedback from the prolonged JNK activation on ERK in these cells (Jeffrey et al, 2006).…”

Anti-inflammatory functions of glucocorticoid-induced genes

“…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 .…”