The Role of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 in the p38/TNF-α Pathway of Systemic and Cutaneous Inflammation

Schottelius, Arndt; Zügel, Ulrich; Döcke, Wolf‐Dietrich; Zollner, Thomas M.; Röse, Lars; Mengel, Anne; Buchmann, Bernd; Becker, Andreas; Grütz, Gerald; Naundorf, Sandra; Friedrich, Anette; Gaestel, Matthias; Asadullah, Khusru

doi:10.1038/jid.2009.218

Cited by 38 publications

(35 citation statements)

References 31 publications

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“…By these means, DCs help to limit inflammatory processes and turn off excessive immune responses, thereby preventing damage to the host system. In line with our observations, locally distinct proinflammatory responses were induced in disease models propagating cutaneous or lung inflammation in systemic MK2-deficient mice in a tissue-dependent manner (13,42). These heterogeneous responses may result from variable expression patterns in different cell types and cellular context dependency of MK2.…”

Section: Discussionsupporting

confidence: 71%

The MAPK-Activated Kinase MK2 Attenuates Dendritic Cell–Mediated Th1 Differentiation and Autoimmune Encephalomyelitis

Soukup

Halfmann

Bras

et al. 2015

The Journal of Immunology

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Dendritic cell (DC)–mediated inflammation induced via TLRs is promoted by MAPK-activated protein kinase (MK)-2, a substrate of p38 MAPK. In this study we show an opposing role of MK2, by which it consolidates immune regulatory functions in DCs through modulation of p38, ERK1/2-MAPK, and STAT3 signaling. During primary TLR/p38 signaling, MK2 mediates the inhibition of p38 activation and positively cross-regulates ERK1/2 activity, leading to a reduction of IL-12 and IL-1α/β secretion. Consequently, MK2 impairs secondary autocrine IL-1α signaling in DCs, which further decreases the IL-1α/p38 but increases the anti-inflammatory IL-10/STAT3 signaling route. Therefore, the blockade of MK2 activity enables human and murine DCs to strengthen proinflammatory effector mechanisms by promoting IL-1α–mediated Th1 effector functions in vitro. Furthermore, MK2-deficient DCs trigger Th1 differentiation and Ag-specific cytotoxicity in vivo. Finally, wild-type mice immunized with LPS in the presence of an MK2 inhibitor strongly accumulate Th1 cells in their lymph nodes. These observations correlate with a severe clinical course in DC-specific MK2 knockout mice compared with wild-type littermates upon induction of experimental autoimmune encephalitis. Our data suggest that MK2 exerts a profound anti-inflammatory effect that prevents DCs from prolonging excessive Th1 effector T cell functions and autoimmunity.

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Section: Discussionsupporting

confidence: 71%

The MAPK-Activated Kinase MK2 Attenuates Dendritic Cell–Mediated Th1 Differentiation and Autoimmune Encephalomyelitis

Soukup

Halfmann

Bras

et al. 2015

The Journal of Immunology

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“…In contrast, MSK1 ⁄ 2 have been demonstrated to play an essential role in the resolution of acute inflammation as it was demonstrated that wild-type mice exhibited a steady decline in inflammation 24-96 h post challenge, whereas the MSK1 ⁄ 2 knockout mice failed to improve 12-O-tetradecanoyl phorbol 13-acetate TPA-induced inflammation (15). Although Schottelius et al (33) recently showed that the biological role of a kinase may be heterogeneous depending on the type of skin inflammation model used, MSK1 ⁄ 2 acts as negative regulators of skin inflammation in both the chronic allergic contact dermatitis model as shown in this study as well as the acute TPA skin model as shown in a previous study (15).…”

Section: Discussionmentioning

confidence: 98%

The role of mitogen‐ and stress‐activated protein kinase 1 and 2 in chronic skin inflammation in mice

Bertelsen¹,

Iversen²,

Riis³

et al. 2010

Experimental Dermatology

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Mitogen-and stress-activated protein kinase 1 and 2 (MSK1 ⁄ 2) are two kinases phosphorylated by both ERK1 ⁄ 2 and p38 MAPK. Recently, MSK1 and 2 have been reported to act as negative regulators of acute inflammation. In this study, we investigated the role of MSK1 ⁄ 2 in chronic skin inflammation using an oxazolone-induced allergic contact dermatitis model in MSK1 ⁄ 2 knockout mice and wild-type mice. MSK1 ⁄ 2 knockout mice were demonstrated to have significantly increased inflammation compared with wild-type mice. This was measured by an increased ear thickness, elevated infiltration of neutrophils in the skin and increased inflammatory histological changes. Furthermore, we found significantly elevated levels of the proinflammatory cytokines Tumor necrosis factor-a (TNF-a), IL-1b and IL-6 at both mRNA and protein levels in MSK1 ⁄ 2 knockout mice compared with wild-type mice after oxazolone treatment. In addition, the mRNA expression of the chemokine Thymus and activation regulated chemokine (TARC) was demonstrated to be significantly elevated in oxazolone-treated MSK1 ⁄ 2 knockout mice compared with wild-type mice. The increased expression of TARC was paralleled by increased infiltration of cells positive for the TARC receptor, CCR4, in the dermis of MSK1 ⁄ 2 knockout mice. Our results indicate that MSK1 ⁄ 2 are involved in the activation of feedback mechanisms that dampen oxazolone-induced skin inflammation.

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“…TNF-α, a 17-kDa protein, which was first identified as a product of activated macrophages, is a well-known proinflammatory cytokine 25) and it is involved in various inflammations 11,26) . Recently, evidence has been provided of the widespread role of TNF-α in mediating hyperalgesia at different levels 8) , both facilitating neuronal excitability and triggering the release of other pro-inflammatory substances 9,10) .…”

Section: Discussionmentioning

confidence: 99%

Effects of Magnetic Infrared Laser Irradiation on Formalin-Induced Chronic Paw Inflammation of Mice

et al. 2010

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Abstract.[Purpose] The purpose of the present study was to investigate the effect of magnetic infrared laser (MIL) irradiation on formalin-induced chronic inflammation.[Subjects] Male ICR mice. [Methods] Mice were subaponeurotically injected in the left hind paw with 0.02 ml of 3.75% formalin, then subjected to 1.33, 2.66 and 6.65 J/cm 2 of MIL irradiation, once a day for 10 days during which then the hind-paw thickness and volume were measured daily. The paw wet-weight, histological profiles, histomorphometrical analyses and paw tumor necrosis factor (TNF)-α contents were conducted at termination and compared with those of dexamethasone, 15 mg/kg, intraperitoneally injected mice.[Results] After two formalin treatments, a marked increase in the paw thickness and volume was detected in the formalin-injected control as compared with the vehicle control. Also at the time of sacrifice the paw wet-weights, and paw TNF-α contents were also dramatically increased and confirmed by histopathological observations. However, these formalin-induced chronic inflammatory changes were significantly and dose-dependently decreased by MIL irradiation.[Conclusion] MIL radiation has favorable effects on formalin-induced chronic inflammation mediated by TNF-α suppression, and MIL therapy may represent an alternative approach for the treatment of chronic inflammatory diseases.

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The Role of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 in the p38/TNF-α Pathway of Systemic and Cutaneous Inflammation

Cited by 38 publications

References 31 publications

The MAPK-Activated Kinase MK2 Attenuates Dendritic Cell–Mediated Th1 Differentiation and Autoimmune Encephalomyelitis

The MAPK-Activated Kinase MK2 Attenuates Dendritic Cell–Mediated Th1 Differentiation and Autoimmune Encephalomyelitis

The role of mitogen‐ and stress‐activated protein kinase 1 and 2 in chronic skin inflammation in mice

Effects of Magnetic Infrared Laser Irradiation on Formalin-Induced Chronic Paw Inflammation of Mice

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