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Caffeine Inhibits NLRP3 Inflammasome Activation by Suppressing MAPK/NF-?B and A2aR Signaling in LPS-Induced THP-1 Macrophages.

ABSTRACT: Excessive inflammation induced by various risk factors is associated with the development of bronchopulmonary dysplasia (BPD). Caffeine exerts potent anti-inflammatory effects as a clinical preventive medicine for BPD. Recently, NLRP3 inflammasome activation has been demonstrated to be essential for the pathogenesis of BPD. In the present study, we aimed to investigate the effects of caffeine on NLRP3 inflammasome activation in LPS-induced THP-1 macrophages and to explore the underlying the detailed mechanism. We found that caffeine significantly reduced NLRP3 expression, ASC speck formation, and caspase 1 cleavage and therefore decreased IL-1? and IL-18 secretion in THP-1 macrophages. Caffeine also markedly decreased the phosphorylation levels of MAPK and NF-?B pathway members, further suppressing the translocation of NF-?B in THP-1 macrophages. Moreover, silencing of the caffeine-antagonized adenosine A2a receptor (A2aR) significantly decreased cleaved caspase 1 expression in THP-1 macrophages by reducing ROS production. Given these findings, we conclude that caffeine inhibits NLRP3 inflammasome activation by suppressing MAPK/NF-?B signaling and A2aR-associated ROS production in LPS-induced THP-1 macrophages.

SUBMITTER: Zhao W

PROVIDER: S-EPMC6643212 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Caffeine Inhibits NLRP3 Inflammasome Activation by Suppressing MAPK/NF-κB and A2aR Signaling in LPS-Induced THP-1 Macrophages.

Zhao Weiming W Ma Li L Cai Cheng C Gong Xiaohui X

International journal of biological sciences 20190602 8

Excessive inflammation induced by various risk factors is associated with the development of bronchopulmonary dysplasia (BPD). Caffeine exerts potent anti-inflammatory effects as a clinical preventive medicine for BPD. Recently, NLRP3 inflammasome activation has been demonstrated to be essential for the pathogenesis of BPD. In the present study, we aimed to investigate the effects of caffeine on NLRP3 inflammasome activation in LPS-induced THP-1 macrophages and to explore the underlying the deta ...[more]

PMID: 31360100

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Project description:Background: Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a common respiratory disease characterized by persistent hypoxemia and an uncontrolled inflammatory response. Valsartan, an angiotensin II type 1 receptor antagonist, is clinically used to treat hypertension and has anti-inflammatory and antioxidant effects on gefitinib-induced pneumonia in rats. However, the potential therapeutic effects of valsartan on lipopolysaccharide (LPS)-induced ALI remain unclear. This study investigated the protective role of valsartan in LPS-induced ALI and its underlying mechanisms. Methods: LPS-treated BEAS-2B cells and ALI mouse model were established. BEAS-2B cells were treated with LPS (10 μg/mL) for 24h, with or without valsartan (20, 40, and 80 µM). For ALI mouse models, LPS (5 mg/kg) was administered through intratracheal injection to treat the mice for 24h, and valsartan (10 or 30 mg/kg) was injected intraperitoneally twice 2 h before and 12 h after the LPS injection. Pulmonary functional parameters were examined by an EMKA pulmonary system. Hematoxylin and eosin staining, flow cytometry, CCK-8 assay, qRT-PCR, ELISA, immunofluorescence, Western blotting, and related commercial kits were used to assess the pathological damage to the lungs, neutrophil recruitment in the lung tissue and bronchoalveolar lavage fluid (BALF), cell viability, inflammation, oxidative activity, and mucus production, respectively. Potential mechanisms were further explored using network pharmacology and Western blotting. Results: Valsartan rescued LPS-reduced cell viability of BEAS-2B cells, improved the pulmonary function, ameliorated pathological lung injury in mice with ALI, ameliorated LPS-induced neutrophil recruitment in BALF and lung tissue of mice, attenuated oxidative stress by increasing the level of SOD and decreasing that of MDA and GSSG, inhibited LPS-induced MUC5AC overproduction, decreased the LPS-induced increase in expression of pro-inflammatory cytokines/chemokines including TNF-α, IL-6, IL-1β, CXCL-1 and CXCL-2, and restored the expression of anti-inflammatory IL-10. Mechanistic studies showed that valsartan inhibits LPS-induced phosphorylation of nuclear factor-kappa B (NF-κΒ) and mitogen-activated protein kinases (MAPKs) including P38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) in both LPS-treated cells and the mouse model of ALI. Conclusion: Valsartan protects against LPS-induced ALI by attenuating oxidative stress, reducing MUC5AC production, and attenuating the inflammatory response that may involve MAPK and NF-κΒ pathways.

Dataset Information

Caffeine Inhibits NLRP3 Inflammasome Activation by Suppressing MAPK/NF-?B and A2aR Signaling in LPS-Induced THP-1 Macrophages.

Publications

Caffeine Inhibits NLRP3 Inflammasome Activation by Suppressing MAPK/NF-κB and A2aR Signaling in LPS-Induced THP-1 Macrophages.

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