Please use this identifier to cite or link to this item: https://doi.org/10.1186/ar2810
Title: Suppressive effect of secretory phospholipase A2inhibitory peptide on interleukin-1β-induced matrix metalloproteinase production in rheumatoid synovial fibroblasts, and its antiarthritic activity in hTNFtg mice
Authors: Thwin M.-M. 
Douni E.
Arjunan P. 
Kollias G.
Kumar P.V. 
Gopalakrishnakone P. 
Keywords: antiflamin 2
antirheumatic agent
celecoxib
gelatinase A
gelatinase B
infliximab
interleukin 1beta
interleukin 6
interstitial collagenase
matrix metalloproteinase
matrix metalloproteinase inhibitor
messenger RNA
methotrexate
mitogen activated protein kinase p38
phospholipase A2 group II
phospholipase A2 group IIA
phospholipase A2 inhibitor
phospholipase inhibitor from python 18
stromelysin
synthetic peptide
tissue inhibitor of metalloproteinase 1
tissue inhibitor of metalloproteinase 2
tumor necrosis factor
tumor necrosis factor alpha
unclassified drug
varespladib
enzyme inhibitor
matrix metalloproteinase
peptide
secretory phospholipase A2
tumor necrosis factor alpha
animal cell
animal experiment
animal model
animal tissue
ankle
article
cell stimulation
concentration response
controlled study
drug effect
drug efficacy
drug mechanism
enzyme activity
enzyme inhibition
enzyme linked immunosorbent assay
enzyme phosphorylation
enzyme synthesis
fibroblast culture
gene expression
histopathology
human
human cell
human tissue
mouse
nonhuman
osteoarthritis
protein expression
real time polymerase chain reaction
rheumatoid arthritis
RNA transcription
synoviocyte
animal
biosynthesis
cytology
drug antagonism
fibroblast
genetic transcription
genetics
metabolism
reverse transcription polymerase chain reaction
synovium
transgenic mouse
Animals
Arthritis, Rheumatoid
Enzyme Inhibitors
Enzyme-Linked Immunosorbent Assay
Fibroblasts
Gene Expression
Humans
Interleukin-1beta
Matrix Metalloproteinases
Mice
Mice, Transgenic
Peptides
Phospholipases A2, Secretory
Reverse Transcriptase Polymerase Chain Reaction
Synovial Membrane
Transcription, Genetic
Tumor Necrosis Factor-alpha
Issue Date: 2009
Publisher: BioMed Central Ltd.
Citation: Thwin M.-M., Douni E., Arjunan P., Kollias G., Kumar P.V., Gopalakrishnakone P. (2009). Suppressive effect of secretory phospholipase A2inhibitory peptide on interleukin-1β-induced matrix metalloproteinase production in rheumatoid synovial fibroblasts, and its antiarthritic activity in hTNFtg mice. Arthritis Research and Therapy 11 (5) : R138. ScholarBank@NUS Repository. https://doi.org/10.1186/ar2810
Abstract: Introduction: Secretory phospholipase A2(sPLA2) and matrix metalloproteinase (MMP) inhibitors are potent modulators of inflammation with therapeutic potential, but have limited efficacy in rheumatoid arthritis (RA). The objective of this study was to understand the inhibitory mechanism of phospholipase inhibitor from python (PIP)-18 peptide in cultured synovial fibroblasts (SF), and to evaluate its therapeutic potential in a human tumor necrosis factor (hTNF)-driven transgenic mouse (Tg197) model of arthritis.Methods: Gene and protein expression of sPLA2-IIA, MMP-1, MMP-2, MMP-3, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1, and TIMP-2 were analyzed by real time PCR and ELISA respectively, in interleukin (IL)-1? stimulated rheumatoid arthritis (RA) and osteoarthritis (OA) synovial fibroblasts cells treated with or without inhibitors of sPLA2 (PIP-18, LY315920) or MMPs (MMP Inhibitor II). Phosphorylation status of mitogen-activated protein kinase (MAPK) proteins was examined by cell-based ELISA. The effect of PIP-18 was compared with that of celecoxib, methotrexate, infliximab and antiflamin-2 in Tg197 mice after ip administration (thrice weekly for 5 weeks) at two doses (10, 30 mg/kg), and histologic analysis of ankle joints. Serum sPLA2and cytokines (tumor necrosis factor (TNF)?, IL-6) were measured by Escherichia coli (E coli) assay and ELISA, respectively.Results: PIP-18 inhibited sPLA2-IIA production and enzymatic activity, and suppressed production of MMPs in IL-1?-induced RA and OA SF cells. Treatment with PIP-18 blocked IL-1?-induced p38 MAPK phosphorylation and resulted in attenuation of sPLA2-IIA and MMP mRNA transcription in RA SF cells. The disease modifying effect of PIP-18 was evidenced by significant abrogation of synovitis, cartilage degradation and bone erosion in hTNF Tg197 mice.Conclusions: Our results demonstrate the benefit that can be gained from using sPLA2inhibitory peptide for RA treatment, and validate PIP-18 as a potential therapeutic in a clinically relevant animal model of human arthritis. © 2009 Thwin et al.; licensee BioMed Central Ltd.
Source Title: Arthritis Research and Therapy
URI: https://scholarbank.nus.edu.sg/handle/10635/174461
ISSN: 14786354
DOI: 10.1186/ar2810
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