p38γ and p38δ kinases regulate the Toll-like receptor 4 (TLR4)-induced cytokine production by controlling ERK1/2 protein kinase pathway activation

Risco, Ana Marı́a; Fresno, Carlos del; Mambol, Agnes; Alsina‐Beauchamp, Dayanira; MacKenzie, Kirsty F.; Yang, Huei-Ting; Barber, Domingo F.; Morcelle, Carmen; Arthur, J. Simon C.; Ley, Steven C.; Ardavı́n, Carlos; Cuenda, Ana

doi:10.1073/pnas.1207290109

Cited by 106 publications

(157 citation statements)

References 39 publications

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“…Recent emerging studies suggest that p38␤ signaling may play a critical role in cell survival and the reversal of inflammatory responses (42). p38␦ and p38␥ isoforms have been shown to regulate transcription of genes (43). Because we observed endothelial expression of ␣, ␤, and ␥ isoforms of p38 MAPK, we attempted to identify the isoform(s) activated downstream of AMPK in response to thrombin-induced SOCE in HLMVECs.…”

Section: Discussionmentioning

confidence: 99%

Store-operated Ca2+ Entry (SOCE) Induced by Protease-activated Receptor-1 Mediates STIM1 Protein Phosphorylation to Inhibit SOCE in Endothelial Cells through AMP-activated Protein Kinase and p38β Mitogen-activated Protein Kinase

Sundivakkam

Natarajan

Malik

et al. 2013

Journal of Biological Chemistry

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The Ca2+ sensor STIM1 is crucial for activation of store-operated Ca2+ entry (SOCE) through transient receptor potential canonical and Orai channels. STIM1 phosphorylation serves as an “off switch” for SOCE. However, the signaling pathway for STIM1 phosphorylation is unknown. Here, we show that SOCE activates AMP-activated protein kinase (AMPK); its effector p38β mitogen-activated protein kinase (p38β MAPK) phosphorylates STIM1, thus inhibiting SOCE in human lung microvascular endothelial cells. Activation of AMPK using 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) resulted in STIM1 phosphorylation on serine residues and prevented protease-activated receptor-1 (PAR-1)-induced Ca2+ entry. Furthermore, AICAR pretreatment blocked PAR-1-induced increase in the permeability of mouse lung microvessels. Activation of SOCE with thrombin caused phosphorylation of isoform α1 but not α2 of the AMPK catalytic subunit. Moreover, knockdown of AMPKα1 augmented SOCE induced by thrombin. Interestingly, SB203580, a selective inhibitor of p38 MAPK, blocked STIM1 phosphorylation and led to sustained STIM1-puncta formation and Ca2+ entry. Of the three p38 MAPK isoforms expressed in endothelial cells, p38β knockdown prevented PAR-1-mediated STIM1 phosphorylation and potentiated SOCE. In addition, inhibition of the SOCE downstream target CaM kinase kinase β (CaMKKβ) or knockdown of AMPKα1 suppressed PAR-1-mediated phosphorylation of p38β and hence STIM1. Thus, our findings demonstrate that SOCE activates CaMKKβ-AMPKα1-p38β MAPK signaling to phosphorylate STIM1, thereby suppressing endothelial SOCE and permeability responses.

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Section: Discussionmentioning

confidence: 99%

Store-operated Ca2+ Entry (SOCE) Induced by Protease-activated Receptor-1 Mediates STIM1 Protein Phosphorylation to Inhibit SOCE in Endothelial Cells through AMP-activated Protein Kinase and p38β Mitogen-activated Protein Kinase

Sundivakkam

Natarajan

Malik

et al. 2013

Journal of Biological Chemistry

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“…The present results assign a new function for MAPK13 and should turn the field to a different strategy for the study of MAPK biology and blockade. Though here again we caution an approach that uses the mouse model, in which MAPK13 has recently been shown to regulate other types of kinase-dependent responses (e.g., TLR4-driven ERK1/2 activation in immune cells) (58).…”

Section: Figurementioning

confidence: 99%

IL-13–induced airway mucus production is attenuated by MAPK13 inhibition

Alevy

Patel²,

Romero³

et al. 2012

J. Clin. Invest.

165

234

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Increased mucus production is a common cause of morbidity and mortality in inflammatory airway diseases, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. However, the precise molecular mechanisms for pathogenic mucus production are largely undetermined. Accordingly, there are no specific and effective anti-mucus therapeutics. Here, we define a signaling pathway from chloride channel calcium-activated 1 (CLCA1) to MAPK13 that is responsible for IL-13-driven mucus production in human airway epithelial cells. The same pathway was also highly activated in the lungs of humans with excess mucus production due to COPD. We further validated the pathway by using structure-based drug design to develop a series of novel MAPK13 inhibitors with nanomolar potency that effectively reduced mucus production in human airway epithelial cells. These results uncover and validate a new pathway for regulating mucus production as well as a corresponding therapeutic approach to mucus overproduction in inflammatory airway diseases.

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“…In addition to NF-κB activation, TLR-4 can initiate MAPK signaling (Risco et al, 2012;Hines et al, 2013). Phosphorylation of MAPK family members including ERK, p38, and JNK activates a series of transcription factors, such as activator protein 1 (AP-1), cAMP-response element binding protein (CREB), and signal transducers and activators of transcription (STAT), and subsequently promotes transcription of cytokines (Morimoto et al, 2009;Ruimi et al, 2010).…”

Section: Fig 6 Effect Of Punicalagin On Lps-induced Mapk Activationmentioning

confidence: 99%

Punicalagin protects bovine endometrial epithelial cells against lipopolysaccharide-induced inflammatory injury

Lyu

Chen

Wang

et al. 2017

J. Zhejiang Univ. Sci. B

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Abstract:Objective: Bovine endometritis is one of the most common reproductive disorders in cattle. The aim of this study was to investigate the anti-inflammation potential of punicalagin in lipopolysaccharide (LPS)-induced bovine endometrial epithelial cells (bEECs) and to uncover the underlying mechanisms. Methods: bEECs were stimulated with different concentrations (1, 10, 30, 50, and 100 μg/ml) of LPS for 3, 6, 9, 12, and 18 h. MTT assay was used to assess cell viability and to identify the conditions for inflammatory injury and effective concentrations of punicalagin. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to assess gene expression of pro-inflammatory cytokines. Western blotting was used to assess levels of inflammation-related proteins. Results: Treatment of bEECs with 30 µg/ml LPS for 12 h induced cell injury and reduced cell viability. Punicalagin (5, 10, or 20 µg/ml) pretreatment significantly decreased LPS-induced productions of interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor-α (TNF-α) in bEECs. Molecular research showed that punicalagin inhibited the activation of the upstream mediator nuclear factor-κB (NF-κB) by suppressing the production of inhibitor κBα (IκBα) and phosphorylation of p65. Results also indicated that punicalagin can suppress the phosphorylation of mitogen-activated protein kinases (MAPKs) including p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK). Conclusions: Punicalagin may attenuate LPS-induced inflammatory injury and provide a potential option for the treatment of dairy cows with Escherichia coli endometritis.

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p38γ and p38δ kinases regulate the Toll-like receptor 4 (TLR4)-induced cytokine production by controlling ERK1/2 protein kinase pathway activation

Cited by 106 publications

References 39 publications

Store-operated Ca2+ Entry (SOCE) Induced by Protease-activated Receptor-1 Mediates STIM1 Protein Phosphorylation to Inhibit SOCE in Endothelial Cells through AMP-activated Protein Kinase and p38β Mitogen-activated Protein Kinase

Store-operated Ca2+ Entry (SOCE) Induced by Protease-activated Receptor-1 Mediates STIM1 Protein Phosphorylation to Inhibit SOCE in Endothelial Cells through AMP-activated Protein Kinase and p38β Mitogen-activated Protein Kinase

IL-13–induced airway mucus production is attenuated by MAPK13 inhibition

Punicalagin protects bovine endometrial epithelial cells against lipopolysaccharide-induced inflammatory injury

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