Cytosolic Phospholipase A2 Regulates TNF-Induced Production of Joint Destructive Effectors in Synoviocytes

Sommerfelt, Randi Magnus; Feuerherm, Astrid Jullumstrø; Jones, Kymry T.; Johansen, Berit

doi:10.1371/journal.pone.0083555

Cited by 32 publications

(31 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To investigate the roles of sPLA2s and cPLA2α in TLR2-induced synoviocyte AA release and PGE 2 production, we next analyzed the effects of synthetic inhibitors of cPLA2α (Inhibitor 28 [ 36 ], CAY10502 [ 37 ], AVX002 [ 38 , 39 ], ATK [ 40 ],) or sPLA2 (CAY10590 [ 41 ], Varespladib [ 42 ]). In response to both TLR2 ligands, all cPLA2α inhibitors efficiently reduced AA release to untreated control level ( Fig 4D ).…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, cPLA2α inhibition effectively attenuated the TLR-induced AA release and PGE 2 production, suggesting a central role for cPLA2α in synoviocyte AA metabolism. cPLA2α is expressed in RA synovium and cultured FLS, and its transcription is induced by various pro-inflammatory stimuli, including IL-1β, TNF and lipopolysaccharide [ 30 , 39 , 47 ]. Here, we report that TLR2/1 and TLR2/6 ligands induce synoviocyte cPLA2α gene transcription, indicating that TLR2 ligands activate cPLA2α-dependent AA mobilization directly by increased enzyme activity, and indirectly by transcriptional regulation and de novo synthesis as previously described [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Cytosolic Phospholipase A2 Modulates TLR2 Signaling in Synoviocytes

et al. 2015

Self Cite

View full text Add to dashboard Cite

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovitis leading to destruction of cartilage and bone. PLA2 enzymes are key players in inflammation regulating the release of unsaturated fatty acids such as arachidonic acid (AA), a precursor of pro-inflammatory eicosanoids. Several lines of evidence point to toll-like receptors (TLRs) as drivers of synovitis and joint destruction in RA. However, few studies have addressed the implication of PLA2 activity downstream TLR activation in the synovium. Here, we aimed to characterize PLA2 enzyme involvement in TLR2-induced signaling in synovial fibroblast-like cells. TLRs1-7 and a range of sPLA2, iPLA2 and cPLA2 enzymes were found to be transcriptionally expressed in cultured synoviocytes. Activation of TLR2/1 and TLR2/6 led to phosphorylation of cPLA2α at Ser505, and induced AA release and PGE2 production; effects that were attenuated by cPLA2α inhibitors. In contrast, sPLA2 inhibitors did not affect AA or PGE2 release. cPLA2α inhibitors furthermore attenuated TLR-induced expression of IL-6, IL-8 and COX2. COX1/2 inhibitors attenuated TLR2/6-induced IL-6 transcription and protein production comparable to cPLA2α inhibition. Moreover, exogenously PGE2 added alone induced IL-6 production and completely rescued IL-6 transcription when added simultaneously with FSL-1 in the presence of a cPLA2α inhibitor. Our results demonstrate for the first time that cPLA2α is involved in TLR2/1- and TLR2/6-induced AA release, PGE2 production and pro-inflammatory cytokine expression in synoviocytes, possibly through COX/PGE2-dependent pathways. These findings expand our understanding of cPLA2α as a modulator of inflammatory molecular mechanisms in chronic diseases such as RA.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cytosolic Phospholipase A2 Modulates TLR2 Signaling in Synoviocytes

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…Similar to TNF-α, cPLA2 is also known to play an important role in regulating autoimmune diseases 43,44 . cPLA2 is implicated in synovitis and joint destruction in rheumatoid arthritis by regulating the production of inflammatory mediators 45 . cPLA2 up-regulation leads to a greater disease severity phenotype in the DSS-induced colitis mouse model, whereas intravenous administration of antisense oligonucleotides against cPLA2 prevents disease development, suppresses NF-κB activation, and decreases expressions of pro-inflammatory proteins 46 , indicating the potential treatment target role of cPLA2 in colitis.…”

Section: Tnf-α Regulation Of Immune Cells Such As Macrophage Polarizmentioning

confidence: 99%

Fexofenadine inhibits TNF signaling through targeting to cytosolic phospholipase A2 and is therapeutic against autoimmune diseases

R¹,

Chen²,

Wang³

et al. 2019

Preprint

View full text Add to dashboard Cite

SUMMARYTNF-α signaling plays a central role in the pathogenesis of various diseases, particularly autoimmune diseases. Screening of a library composed of FDA approved drugs led to the identification of Terfenadine and its active metabolite Fexofenadine as inhibitors of TNF-α signaling. Both Fexofenadine and Terfenadine inhibited TNF/NF-κB signaling in vitro and in vivo, and ameliorated disease symptoms in various autoimmune disease models, including TNF-α transgenic mice, collagen-induced arthritis, and inflammatory bowel disease. Subsequent studies identified cytosolic phospholipase A2 (cPLA2) as a novel target of Fexofenadine. Fexofenadine blocked TNF-stimulated cPLA2 activity and arachidonic acid production through binding to catalytic domain 2 of cPLA2 and inhibition of its phosphorylation on Ser-505. Further, deletion of cPLA2 abolished Fexofenadine’s anti-TNF activity. Collectively, these findings not only provide new insights into the understanding of Fexofenadine action and underlying mechanism, but also provide new therapeutic interventions for various TNF-α and cPLA2-associated pathologies and conditions, particularly autoimmune diseases.

show abstract

“…Inflammatory mediators such as TNF are elevated in the joints 36 and tears 35 in patients with RA. The impor tance of TNF in this context was illustrated by clinical improvement in sightthreatening ocular surface disease in RA such as scleritis and peripheral ulcerative keratitis after treatment with infliximab (a monoclonal antibody against TNF).…”

Section: Clinical Evidencementioning

confidence: 99%

The eye: a window of opportunity in rheumatoid arthritis?

et al. 2014

View full text Add to dashboard Cite

Rheumatoid arthritis (RA), the most common autoimmune disorder associated with dry eye syndrome, is also associated with sight-threatening ocular diseases such as peripheral ulcerative keratitis, scleritis and corneal melts. Tissue damage on the ocular surface of patients with RA is autoimmune-mediated. Findings from patients with dry eye have implicated defects in innate immunity (Toll-like receptors, S100A and resident antigen-presenting cells), cytokines, chemokines and T helper (TH)-cell subsets (including TH1 and TH17) in disease pathogenesis. Some of these features are probably important in dry eye related to RA, which can occur at a different time from articular disease and is more clinically severe than idiopathic dry eye. Ocular surface immune factors can be influenced by the systemic immune landscape. Depending on the severity of ocular inflammation in RA, treatment can include ciclosporin, topical corticosteroids, tacrolimus, autologous serum and systemic immunosuppression. Tissue damage is treated by inhibiting matrix metalloproteinases. Potential therapeutic strategies benefit from an improved understanding of ocular surface immunology, and include targeting of T-cell subsets, B-cell signalling or cytokines.

show abstract

Cytosolic Phospholipase A2 Regulates TNF-Induced Production of Joint Destructive Effectors in Synoviocytes

Cited by 32 publications

References 53 publications

Cytosolic Phospholipase A2 Modulates TLR2 Signaling in Synoviocytes

Cytosolic Phospholipase A2 Modulates TLR2 Signaling in Synoviocytes

Fexofenadine inhibits TNF signaling through targeting to cytosolic phospholipase A2 and is therapeutic against autoimmune diseases

The eye: a window of opportunity in rheumatoid arthritis?

Contact Info

Product

Resources

About