Differential regulation of TNFα and GM-CSF induced activation of P38 MAPK in neutrophils and eosinophils

Hove, Willem ten; Houben, L. A. M. J.; Raaijmakers, J. A. M.; Bracke, Madelon; Koenderman, Leo

doi:10.1016/j.molimm.2006.10.009

Cited by 15 publications

(10 citation statements)

References 24 publications

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“…The link between the TNF receptor (TNFR) and p38 MAPK activation has been previously reported [32,33]. Ligations of the TNFR phosphorylate MKK3/MKK6, upstream of p38 MAPK, have also been shown [34,35]. Therefore, we speculate that autocrine activation by TNF-α caused the phosphorylation of p38 MAPK.…”

Section: Discussionmentioning

confidence: 66%

A Possible Mechanism of Cisplatin-Induced Tumor Necrosis Factor (TNF)-α Production in Murine Macrophages

Kim¹,

Yamamoto²,

Nakamura³

et al. 2013

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Cisplatin has been used for the treatment of various solid cancers or sarcomas; however, it can induce severe adverse effects. Among these adverse effects, nephrotoxicity, which has the potential to be a dose-limiting factor of this agent, develops due to the secretion of tumor necrosis factor-α (TNF-α) from macrophages; however, the precise mechanisms are still unclear. To elucidate possible mechanisms, we investigated the involvement of mitogen-activated protein kinases (MAPK) and reactive oxygen species (ROS) in cisplatin-induced TNF-α mRNA expression and protein production in the mouse macrophage-like cell line, RAW 264. Cisplatin (1 μM) significantly increased TNF-α mRNA expression and protein production. Extracellular-regulated kinase (ERK) and p38 MAPK, but not c-Jun N-terminal kinase (JNK), phosphorylation increased in response to cisplatin. Although an ERK inhibitor (PD98059) suppressed both cisplatin-induced TNF-α mRNA expression and its protein production, a p38 MAPK inhibitor (SB203580) decreased TNF-α protein production only. A JNK inhibitor (SP600125) had no effect on cisplatin-induced TNF-α mRNA expression. Furthermore, a scavenger of ROS, N,N'-dimethylthiourea, suppressed both ERK activation and TNF-α mRNA expression. These results suggest that the phosphorylation of ERK by ROS is involved in cisplatin-induced TNF-α mRNA expression and that the signaling pathway of p38 MAPK is related to TNF-α protein production.

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Section: Discussionmentioning

confidence: 66%

A Possible Mechanism of Cisplatin-Induced Tumor Necrosis Factor (TNF)-α Production in Murine Macrophages

Kim¹,

Yamamoto²,

Nakamura³

et al. 2013

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“…Reduction of phosphorylation of p38 itself by Org 48762‐0 and SB203580 (Figure 4b) may have been caused by interference with p38 autophosphorylation in the alternative activation path as suggested by ten Hove et al . (2007) or by compound‐induced conformational change affecting the availability of its phosphorylation sites.…”

Section: Discussionmentioning

confidence: 73%

A potent and selective p38 inhibitor protects against bone damage in murine collagen‐induced arthritis: a comparison with neutralization of mouse TNFα

Mihara¹,

Almansa²,

Smeets³

et al. 2008

British J Pharmacology

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Background and purpose: The p38 kinase regulates the release of proinflammatory cytokines including tumour-necrosis factor-a (TNFa) and is regarded as a potential therapeutic target in rheumatoid arthritis (RA). Using the novel p38 inhibitor Org 48762-0, we investigated the therapeutic potential of p38 inhibition and compared this to anti-mouse (m)TNFa antibody treatment in murine collagen-induced arthritis (CIA). Experimental approach: Pharmacological profiles of Org 48762-0 were characterized in kinase assays, cellular assays and in lipopolysaccharide (LPS)-induced inflammation in mice. The effects of Org 48762-0 and of mTNFa-neutralization on established arthritis were examined in murine CIA. Key results: Org 48762-0 potently inhibited p38a kinase with a high degree of kinase selectivity. In cellular assays, Org 48762-0 reduced LPS-induced TNFa release. Oral administration of Org 48762-0 in mice showed drug-like pharmacokinetic properties and inhibited LPS-induced cytokine production. These pharmacological characteristics of Org 48762-0 prompted a comparison of therapeutic efficacy with mTNFa-neutralization in CIA. Org 48762-0 and anti-mTNFa antibody treatment equally inhibited development of arthritis when evaluated macroscopically. Radiological analyses revealed protection against bone damage for both treatments, although statistical difference was reached with Org 48762-0 treatment only. Further, micro-computed tomographical and histopathological analyses confirmed the protective effects of Org 48762-0 on joint damage. Conclusions and implications: Pharmacological targeting of p38 kinase provided good protection against joint tissue damage in CIA. In our experiments, neutralization of mTNFa produced less prominent suppression of bone damage. Our data suggest a therapeutic potential for selective and potent p38 inhibitors in RA.

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“…MKK3 and MKK6 are both known to phosphorylate p38. Therefore, ligation of TNFR1 in neutrophils results in the phosphorylation and activation of MKK3/MKK6 and subsequently p38, 45,46 and p38 activation after TNF-␣ stimulation induces neutrophil apoptosis. 47 Indirect activation of this signaling cascade by TNF-␣ via adhesion molecules was unlikely in our experiments, because no significant adhesion of neutrophils occurred under the culture conditions used (ie, the presence of 5% FCS).…”

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confidence: 99%

A novel TNFR1-triggered apoptosis pathway mediated by class IA PI3Ks in neutrophils

Geering

Gurzeler

Federzoni

et al. 2011

Blood

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The most common form of neutrophil death is apoptosis. In the present study, we report surprising differences in the molecular mechanisms used for caspase activation between FAS/CD95-stimulated and TNF receptor 1 (TNFR1)-stimulated neutrophils. Whereas FAS-induced apoptosis was followed by caspase-8 activation and required Bid to initiate the mitochondrial amplification loop, TNF-␣-induced apoptosis involved class IA PI3Ks, which were activated by MAPK p38. TNF-␣-induced PI3K activation resulted in the generation of reactive oxygen species, which activated caspase-3, a mechanism that did not operate in neutrophils without active NADPH oxidase. We conclude that in neutrophils, proapoptotic pathways after TNFR1 stimulation are initiated by p38 and PI3K, but not by caspase-8, a finding that should be considered in anti-inflammatory drug-development strategies. (Blood. 2011;117(22): 5953-5962) IntroductionNeutrophils are the most abundant leukocytes in human blood and are essential in innate immune responses against pathogens. 1 Both in vitro and in vivo, apoptosis is the most common physiologic cause of neutrophil death, preventing the release of histotoxic contents from the dying cell and therefore limiting tissue damage. 2 Moreover, neutrophil apoptosis contributes to the regulation of the duration and intensity of inflammatory responses. 3,4 Activation of neutrophils with members of the TNF cytokine family such as FAS ligand or TNF-␣ can result in apoptosis and might therefore be relevant in controlling inflammation. Whereas apoptosis induction has consistently been reported in neutrophils after stimulation of FAS/CD95, 5 the consequences of TNF-␣ stimulation on the life span of neutrophils is less clear because apoptosis, survival, and no effect have all been described. 5 The diverse outcomes of TNF-␣ stimulation of neutrophils seem to depend on culture conditions, including the concentration of TNF-␣. 6 Whereas exposure to TNF-␣ concentrations below 1 ng/mL results in neutrophil survival, stimulation with concentrations above 10 ng/mL leads to neutrophil apoptosis. 7 Under inflammatory conditions, TNF-␣ concentrations between 1 and 10 ng/mL have been measured in broncho-alveolar fluids of patients suffering from acute respiratory distress syndrome 8 and in the serum and joint fluids of subjects with rheumatoid arthritis, 9 suggesting that local tissue concentrations may even exceed these numbers.The proapoptotic signaling cascades induced by FAS ligand and TNF-␣ have been intensively studied in multiple cellular systems. Whereas at least 2 TNF-␣ receptors exist, proapoptotic TNF-␣ signaling is mediated through TNF receptor 1 (TNFR1). 10 Both FAS and TNFR1 proapoptotic signaling results in caspase-8 activation. 11 Active caspase-8 can process its own pro-caspase and effector pro-caspases such as pro-caspase-3. 12 Caspase-8 can also process the BCL-2 family member BID, which is involved in mitochondrial outer membrane permeabilization characterized by cytochrome c release and subsequent caspase-9 and caspase-3 a...

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Differential regulation of TNFα and GM-CSF induced activation of P38 MAPK in neutrophils and eosinophils

Cited by 15 publications

References 24 publications

A Possible Mechanism of Cisplatin-Induced Tumor Necrosis Factor (TNF)-α Production in Murine Macrophages

A Possible Mechanism of Cisplatin-Induced Tumor Necrosis Factor (TNF)-α Production in Murine Macrophages

A potent and selective p38 inhibitor protects against bone damage in murine collagen‐induced arthritis: a comparison with neutralization of mouse TNFα

A novel TNFR1-triggered apoptosis pathway mediated by class IA PI3Ks in neutrophils

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