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Phospholipase D enzymes facilitate IL-17- and TNFα-induced expression of proinflammatory genes in rheumatoid arthritis synovial fibroblasts (RASF).

Abstract：

:In rheumatoid arthritis, the synovium exhibits fibroblast hyperplasia and dynamic infiltration of activated T cells. Interaction between rheumatoid arthritis synovial fibroblasts (RASF) and T cell subsets such as Th17 cells can stimulate RASF to express IL-6, IL-8, CCL20, and other proinflammatory mediators of joint destruction. PLD enzymes specifically cleave phosphatidyl choline (PC) producing phosphatidic acid (PA) and choline. Agonist-induced PLD activation results in PA synthesis, which is thought to be involved in a variety of rapid cellular responses such as cytokine secretion. Furthermore, the cellular response to TNF-mediated signaling in myeloid cells is in part mediated by PLD1. However, very few studies have examined the role of PLD enzymes in pro-inflammatory responses of RASF to key pathogenic cytokines such as TNF and IL-17. Microarray analysis of RASF showed that phospholipase D1 (PLD1) is among genes significantly induced by IL-17. We therefore hypothesized that PLD1 might have a role in RASF responses to proinflammatory cytokines. We used 1-butanol, PLD1-specific siRNAs, and small molecule inhibitors specific for PLD1 or PLD2, to investigate the possible role of PLD enzymes in basal, IL-17-, and/or TNFα-evoked expression of proinflammatory cytokines and chemokines by RASF. We studied the in vitro responses of RASF to IL-17A and/or TNFα, with particular attention to effects on IL-6, IL-8 and CCL20 mRNA and secretion as determined by RT-QPCR and ELISA, respectively. Transcriptional and prominent post-transcriptional effects were demonstrated, with robust decreases in RASF secretion of IL-6, IL-8, and CCL20 when both PLD isoforms were inhibited together. Moreover, RA synovial biopsy explants cultured in media containing PLD isoform-specific inhibitors showed significantly reduced constitutive secretion of IL-6 and IL-8. PLD enzymes could be promising targets for controlling proinflammatory gene expression in the treatment of RA in view of roles for PLD in cytokine-evoked transcription and secretion/exocytosis.

journal_name

Immunol Lett

journal_title

Immunology letters

authors

Friday SC,Fox DA

doi

10.1016/j.imlet.2016.04.001

subject

Has Abstract

pub_date

2016-06-01 00:00:00

pages

9-18

eissn

0165-2478

issn

1879-0542

pii

S0165-2478(16)30046-3

journal_volume

174

pub_type

杂志文章

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Phospholipase D enzymes facilitate IL-17- and TNFα-induced expression of proinflammatory genes in rheumatoid arthritis synovial fibroblasts (RASF).