A Bifunctional Role for Group IIA Secreted Phospholipase A2 in Human Rheumatoid Fibroblast-like Synoviocyte Arachidonic Acid Metabolism

Bryant, Katherine; Bidgood, Matthew J.; Lei, Pei Wen; Taberner, Megan; Salom, Caroline; Kumar, Vinod; Lee, Lawrence K.; Church, W. Bret; Courtenay, Brett G.; Smart, Brian P.; Gelb, Michael H.; Cahill, Michael A.; Graham, Garry G.; McNeil, H. Patrick; Scott, Kieran F.

doi:10.1074/jbc.m110.123927

Cited by 28 publications

(25 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the presence of a cytokine, the intracellular enzyme cPLA 2 -␣ (cytosolic PLA 2 -␣, Group IVA PLA 2 ) is stimulated, resulting in arachidonic acid flux to COX-2. This together with the hGIIA-mediated increase in COX-2 protein leads to a significant up-regulation of prostaglandin production (9). Importantly, the studies imply that perturbation of this interaction is a plausible mechanism by which hGIIA-mediated eicosanoid production is blocked in these cells by both selective and non-selective signaling inhibitors.…”

Section: Discussionmentioning

confidence: 81%

“…hGIIA Signaling Assay-FLS cells were isolated and cultured from synovial tissue of patients diagnosed with rheumatoid arthritis (14) undergoing joint surgery at St. Vincent's Hospital, Sydney, using procedures approved by the St. Vincent's Hospital Ethics Committee as described (9,10). Cells (passage 3-10) were plated on 96-well microtiter plates (Greiner), grown to 85-95% confluence, and stimulated for 18 h in serum-free media (DMEM/Ham's F-12 with 0.1% BSA, 200 l) with 10 ng/ml TNF (20 l).…”

Section: Methodsmentioning

confidence: 99%

“…However, recent studies show that hGIIA is a bifunctional protein contributing to arachidonic acid metabolism in cells derived from pathological states by acting both as an enzyme capable of releasing arachidonic acid from microvesicles shed by activated cells and as a catalytic activity-independent indirect amplifier of intracellular eicosanoid production through up-regulation of the cytosolic PLA 2 -cyclooxygenase-2 (COX-2) pathway (9). The bifunctional nature of hGIIA in regulating arachidonic acid metabolism raises important questions about the relative contribution of each function to the production of inflammatory mediators and the subsequent promotion of inflammation.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Selective Inhibition of Human Group IIA-secreted Phospholipase A2 (hGIIA) Signaling Reveals Arachidonic Acid Metabolism Is Associated with Colocalization of hGIIA to Vimentin in Rheumatoid Synoviocytes

Lee

Bryant

Bouveret

et al. 2013

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background: Group IIA secreted phospholipase A 2 (hGIIA) is a bifunctional protein that regulates arachidonic acid metabolism by both catalysis-dependent and catalysis-independent mechanisms. Results: Selective inhibition of the catalysis-independent signaling function perturbs a hGIIA-vimentin interaction in rheumatoid synoviocytes. Conclusion:The signaling and catalytic functions of hGIIA are pharmacologically separable. Significance: Functionally selective inhibitors of hGIIA may provide new avenues for investigation and treatment of immunemediated inflammation.

show abstract

Section: Discussionmentioning

confidence: 81%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Selective Inhibition of Human Group IIA-secreted Phospholipase A2 (hGIIA) Signaling Reveals Arachidonic Acid Metabolism Is Associated with Colocalization of hGIIA to Vimentin in Rheumatoid Synoviocytes

Lee

Bryant

Bouveret

et al. 2013

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Alternatively, the regulation of TNF-dependent prostaglandin production by exogenous sPLA 2 -IIA does not depend on its enzymatic activity. Indeed, sPLA 2 -IIA mutant H48Q having only 1% of the sPLA 2 -IIA enzyme activity is as effective as the fully functional enzyme in up-regulating PGE 2 production and in over inducing TNF-mediated COX-2 production [190]. sPLA 2 -IB, sPLA 2 -IIA, sPLA 2 -V and sPLA 2 -X can produce proinflammatory cytokines and chemokines independently of the hydrolytic activity [191].…”

Section: Phospholipases A2mentioning

confidence: 99%

Phospholipases of Mineralization Competent Cells and Matrix Vesicles: Roles in Physiological and Pathological Mineralizations

Mébarek

Abousalham

Magne

et al. 2013

IJMS

View full text Add to dashboard Cite

The present review aims to systematically and critically analyze the current knowledge on phospholipases and their role in physiological and pathological mineralization undertaken by mineralization competent cells. Cellular lipid metabolism plays an important role in biological mineralization. The physiological mechanisms of mineralization are likely to take place in tissues other than in bones and teeth under specific pathological conditions. For instance, vascular calcification in arteries of patients with renal failure, diabetes mellitus or atherosclerosis recapitulates the mechanisms of bone formation. Osteoporosis—a bone resorbing disease—and rheumatoid arthritis originating from the inflammation in the synovium are also affected by cellular lipid metabolism. The focus is on the lipid metabolism due to the effects of dietary lipids on bone health. These and other phenomena indicate that phospholipases may participate in bone remodelling as evidenced by their expression in smooth muscle cells, in bone forming osteoblasts, chondrocytes and in bone resorbing osteoclasts. Among various enzymes involved, phospholipases A1 or A2, phospholipase C, phospholipase D, autotaxin and sphingomyelinase are engaged in membrane lipid remodelling during early stages of mineralization and cell maturation in mineralization-competent cells. Numerous experimental evidences suggested that phospholipases exert their action at various stages of mineralization by affecting intracellular signaling and cell differentiation. The lipid metabolites—such as arachidonic acid, lysophospholipids, and sphingosine-1-phosphate are involved in cell signaling and inflammation reactions. Phospholipases are also important members of the cellular machinery engaged in matrix vesicle (MV) biogenesis and exocytosis. They may favour mineral formation inside MVs, may catalyse MV membrane breakdown necessary for the release of mineral deposits into extracellular matrix (ECM), or participate in hydrolysis of ECM. The biological functions of phospholipases are discussed from the perspective of animal and cellular knockout models, as well as disease implications, development of potent inhibitors and therapeutic interventions.

show abstract

“…The NF-κB pathway, one of the major signaling pathways in FLS, plays a pivotal role in joint inflammation. NF-κB is highly activated in the synovial tissue of patients with RA and in collagen-induced arthritis (CIA) mice [53,54]. NF-κB regulates the expression of various pro-inflammatory mediators,…”

Section: Immune System Disease: Rheumatoid Arthritismentioning

confidence: 99%

Development of Inflammatory Immune Response-Related Drugs Based on G Protein-Coupled Receptor Kinase 2

Han¹,

Li²,

Wang³

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

G protein-coupled receptor kinase 2 (GRK2), as a vital Ser/Thr kinase, is an important regulatory protein in the inflammatory immune response (IIR) by maintaining the balance between the function of inflammatory immune cells and non-conventional inflammatory immune cells and regulating inflammatory immune cell infiltration, inflammatory cytokine secretion, and the signaling associated with endothelial function. However, the imbalance of GRK2 expression and activity plays an important role in the development of IIR-related diseases, such as hypertension, heart failure, Alzheimer’s disease, type 2 diabetes mellitus, insulin resistance, rheumatoid arthritis, thyroid cancer, multiple sclerosis, and liver cancer. Small molecule GRK2 inhibitors, including balanol, Takeda inhibitors, paroxetine and derivatives, M119 and gallein, peptides, RNA aptamers, Raf kinase inhibitory protein, and microRNAs, that can directly inhibit GRK2 kinase activity have been identified by different strategies. This review discusses recent progress in one of the hallmark molecular abnormalities of GRK2 in IIR-related diseases and explores the soft regulation of IIR by innovative drugs reducing the excessive activity of GRK2 to basal levels, without damaging normal physiological function, to ameliorate inflammatory disorders.

show abstract

A Bifunctional Role for Group IIA Secreted Phospholipase A2 in Human Rheumatoid Fibroblast-like Synoviocyte Arachidonic Acid Metabolism

Cited by 28 publications

References 55 publications

Selective Inhibition of Human Group IIA-secreted Phospholipase A2 (hGIIA) Signaling Reveals Arachidonic Acid Metabolism Is Associated with Colocalization of hGIIA to Vimentin in Rheumatoid Synoviocytes

Selective Inhibition of Human Group IIA-secreted Phospholipase A2 (hGIIA) Signaling Reveals Arachidonic Acid Metabolism Is Associated with Colocalization of hGIIA to Vimentin in Rheumatoid Synoviocytes

Phospholipases of Mineralization Competent Cells and Matrix Vesicles: Roles in Physiological and Pathological Mineralizations

Development of Inflammatory Immune Response-Related Drugs Based on G Protein-Coupled Receptor Kinase 2

Contact Info

Product

Resources

About