Pro-inflammatory Cytokines Drive Deregulation of Potassium Channel Expression in Primary Synovial Fibroblasts



Haidar, Omar, O'Neill, Nathanael, Staunton, Caroline A ORCID: 0000-0003-0647-3063, Bavan, Selvan, O'Brien, Fiona, Zouggari, Sarah, Sharif, Umar, Mobasheri, Ali, Kumagai, Kosuke and Barrett-Jolley, Richard ORCID: 0000-0003-0449-9972
(2020) Pro-inflammatory Cytokines Drive Deregulation of Potassium Channel Expression in Primary Synovial Fibroblasts. FRONTIERS IN PHYSIOLOGY, 11. 226-.

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Abstract

The synovium secretes synovial fluid, but is also richly innervated with nociceptors and acts as a gateway between avascular joint tissues and the circulatory system. Resident fibroblast-like synoviocytes' (FLS) calcium-activated potassium channels (<i>K</i> <sub>Ca</sub>) change in activity in arthritis models and this correlates with FLS <i>activation</i>.<h4>Objective</h4>To investigate this activation in an <i>in vitro</i> model of inflammatory arthritis; 72 h treatment with cytokines TNFα and IL1β.<h4>Methods</h4>FLS cells were isolated from rat synovial membranes. We analyzed global changes in FLS mRNA by RNA-sequencing, then focused on FLS ion channel genes and the corresponding FLS electrophysiological phenotype and finally modeling data with ingenuity pathway analysis (IPA) and MATLAB.<h4>Results</h4>IPA showed significant activation of inflammatory, osteoarthritic and calcium signaling canonical pathways by cytokines, and we identified ∼200 channel gene transcripts. The large <i>K</i> <sub>Ca</sub> (BK) channel consists of the pore forming Kcnma1 together with β-subunits. Following cytokine treatment, a significant increase in Kcnma1 RNA abundance was detected by qPCR and changes in several ion channels were detected by RNA-sequencing, including a loss of BK channel β-subunit expression Kcnmb1/2 and an increase in Kcnmb3. In electrophysiological experiments, there was a decrease in over-all current density at 20 mV without change in chord conductance at this potential.<h4>Conclusion</h4>TNFα and IL1β treatment of FLS <i>in vitro</i> recapitulated several common features of inflammatory arthritis at the transcriptomic level, including increase in Kcnma1 and Kcnmb3 gene expression.

Item Type: Article
Uncontrolled Keywords: TNF&#945, IL1&#946, inflammation, synovial fibroblast, ion channel
Depositing User: Symplectic Admin
Date Deposited: 16 Apr 2020 14:52
Last Modified: 18 Jan 2023 23:55
DOI: 10.3389/fphys.2020.00226
Open Access URL: https://www.frontiersin.org/articles/10.3389/fphys...
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3082686