Alleviating airway inflammation by inhibiting ERK-NF-κB signaling pathway by blocking Kv1.3 channels

Zhou, Qianlan; Wang, Tian-Yue; Li, Miao; Shang, Yunxiao

doi:10.1016/j.intimp.2018.07.009

Cited by 25 publications

(15 citation statements)

References 31 publications

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“…Kv1.3 in T lymphocytes is responsible for controlling the membrane potential which is critical for the activation of these immune cells (Veytia-Bucheli et al, 2018). Several studies have confirmed that Kv1.3 is highly expressed in macrophages, microglia, and TEM cells, suggesting that Kv1.3 plays a crucial role in immune and inflammatory responses to human diseases such as multiple sclerosis (MS), rheumatoid arthritis, Type 1 diabetes, and asthma (Toldi et al, 2010;Huang et al, 2017;Tanner et al, 2017;Zhou et al, 2018). In these conditions, the expression of Kv1.3 channels is significantly elevated (Rangaraju et al, 2009), which is beneficial to define the role of Kv1.3 in autoimmune diseases as well as to clarify the significance of developing Kv1.3 blocker drugs.…”

Section: Introductionmentioning

confidence: 99%

Kv1.3 Channel as a Key Therapeutic Target for Neuroinflammatory Diseases: State of the Art and Beyond

Wang

Guo

et al. 2020

Front. Neurosci.

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Section: Introductionmentioning

confidence: 99%

Kv1.3 Channel as a Key Therapeutic Target for Neuroinflammatory Diseases: State of the Art and Beyond

Wang

Guo

et al. 2020

Front. Neurosci.

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“…The Kv1.3 channel is closely associated with MAPK/NF-κB pathways, which play key roles in the production of inﬂammatory cytokines ( 16 , 17 ). Therefore, the effects of FS48 on LPS-stimulated inﬂammatory signaling pathways were investigated by western blot.…”

Section: Resultsmentioning

confidence: 99%

“…These results suggest that FS48 inhibits inflammation by blockade of Kv1.3, which is further confirmed by the fact that both FS48 and MgTx abolish Kv currents regardless of the immunomodulatory agent, LPS ( 12 ). Several studies have shown that the Kv1.3 channel mediates macrophage inflammation through the activation of MAPK/NF-κB signaling pathways ( 16 , 17 , 32 ). In this study, we find that MAPK/NF-κB pathways are activated in LPS-stimulated Raw 264.7 cells.…”

Section: Discussionmentioning

confidence: 99%

Anti-inflammatory effects of FS48, the first potassium channel inhibitor from the salivary glands of the flea Xenopsylla cheopis

Deng

Zeng

Tang

et al. 2021

Journal of Biological Chemistry

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Edited by Mike ShipstonThe voltage-gated potassium (Kv) 1.3 channel plays a crucial role in the immune responsiveness of T-lymphocytes and macrophages, presenting a potential target for treatment of immune-and inflammation related-diseases. FS48, a protein from the rodent flea Xenopsylla cheopis, shares the three disulfide bond feature of scorpion toxins. However, its threedimensional structure and biological function are still unclear. In the present study, the structure of FS48 was evaluated by circular dichroism and homology modeling. We also described its in vitro ion channel activity using patch clamp recording and investigated its anti-inflammatory activity in LPS-induced Raw 264.7 macrophage cells and carrageenaninduced paw edema in mice. FS48 was found to adopt a common αββ structure and contain an atypical dyad motif. It dose-dependently exhibited the Kv1.3 channel in Raw 264.7 and HEK 293T cells, and its ability to block the channel pore was demonstrated by the kinetics of activation and competition binding with tetraethylammonium. FS48 also downregulated the secretion of proinflammatory molecules NO, IL-1β, TNF-α, and IL-6 by Raw 264.7 cells in a manner dependent on Kv1.3 channel blockage and the subsequent inactivation of the MAPK/NF-κB pathways. Finally, we observed that FS48 inhibited the paw edema formation, tissue myeloperoxidase activity, and inflammatory cell infiltrations in carrageenantreated mice. We therefore conclude that FS48 identified from the flea saliva is a novel potassium channel inhibitor displaying anti-inflammatory activity. This discovery will promote understanding of the bloodsucking mechanism of the flea and provide a new template molecule for the design of Kv1.3 channel blockers.Voltage-gated potassium (Kv) channels play an important role in Ca 2+ signaling, action potential repolarization, cellular proliferation, migration and secretion, and cell volume

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“…Several studies have revealed the involvement of ERK in inflammation. ERK induces inflammatory cytokines such as interleukin (IL)-1β, IL-8 and tumor necrosis factor-α (TNF-α) (Kim, 2014;Kurosawa et al, 2000) and participate in various inflammatory disorders such as inflammatory osteolysis (Seo et al, 2010), cystic fibrosis (Verhaeghe et al, 2007), lung inflammatory diseases (Schuh and Pahl, 2009;Wuyts et al, 2003;Zhou et al, 2018) and arthritis (Thalhamer et al, 2008). In addition, it has been reported that inhibition of ERK phosphorylation can decrease neutrophil-dependent inflammation (Senger et al, 2017;Thalhamer et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Time course study of ERK1/2 activity and cell viability in lipopolysaccharide challenged PC12 cells

et al. 2020

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Introduction: Extracellular signal-regulated kinase 1 and 2 (ERK1/2) are important members of mitogen-activated protein kinases (MAPK), which are actively involved in the shaping of cellular responses to different stimuli; however, these responses are somehow contradicting. It is believed that time is a crucial factor in the determination of these effects. Therefore, the present work was designed to obtain a more vivid view about the effect of time on ERK activity and its relation to cell viability. Methods: In the first step, we challenged cultured PC12 cells with different doses of lipopolysaccharides (LPS) for different time intervals (3, 6, 24 and 48h) and the cell viability was checked by MTT test. Thereafter, we cultured the cells in 6-well plates and treated them with the effective dose (10μg/ml) for the abovementioned intervals and the level of ERK phosphorylation, as the active form, was assessed in the Western blotting analysis. Results: The results showed that treating cells with 10μg/ml LPS reduces cell viability after 48h. While being ineffective in shorter periods of time, ERK activity has a fluctuating trend, so that it reaches the highest level at 6h, thereafter it declines to the lowest level at 24h and partially increases again at 48h. Conclusion: These results imply that time is a determinant factor in the activity of ERK and single-point assessments may result in misinterpretation.

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Alleviating airway inflammation by inhibiting ERK-NF-κB signaling pathway by blocking Kv1.3 channels

Cited by 25 publications

References 31 publications

Kv1.3 Channel as a Key Therapeutic Target for Neuroinflammatory Diseases: State of the Art and Beyond

Kv1.3 Channel as a Key Therapeutic Target for Neuroinflammatory Diseases: State of the Art and Beyond

Anti-inflammatory effects of FS48, the first potassium channel inhibitor from the salivary glands of the flea Xenopsylla cheopis

Time course study of ERK1/2 activity and cell viability in lipopolysaccharide challenged PC12 cells

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