A representative metalloprotease induces PGE(2) synthesis in fibroblast-like synoviocytes via the NF-kappa B/COX-2 pathway with amplification by IL-1 beta and the EP4 receptor

Autor(es)

Viana, Mariana N. ^[1] ; Leiguez, Elbio ^[1] ; Gutierrez, Jose M. ^[2] ; Rucavado, Alexandra ^[2] ; Markus, Regina P. ^[3] ; Marcola, Marina ^[3] ; Teixeira, Catarina ^[1] ; Fernandes, Cristina M. ^[1]

Afiliação do(s) autor(es)

^[1] Butantan Inst, Pharmacol Lab, Sao Paulo, SP - Brazil

^[2] Univ Costa Rica, Sch Microbiol, Clodomiro Picado Inst, San Jose - Costa Rica

^[3] Univ Sao Paulo, Inst Biosci, Dept Physiol, Sao Paulo, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: SCIENTIFIC REPORTS; v. 10, n. 1 FEB 24 2020.
• Citações Web of Science: 0

Resumo

Inflammatory joint conditions are characterized by synovial inflammation, which involves activation of fibroblast-like synoviocytes (FLSs) and production of inflammatory mediators and matrix metalloproteases (MMPs) in joints. This study showed that the snake venom metalloprotease (SVMP) BaP1 activates FLSs to produce PGE(2) by a mechanism dependent on COX-2, mPGES-1 and iPLA(2)s. BaP1 also induces IL-1 beta release, which up-regulates the production of PGE(2) at a late stage of the stimulation. Expression of COX-2 and mPGES-1 are induced by BaP1 via activation of NF-kappa B pathway. While NF-kappa B p50 and p65 subunits are involved in up-regulation of COX-2 expression, only p65 is involved in BaP1-nduced mPGES-1 expression. In addition, BaP1 up-regulates EP4 receptor expression. Engagement of this receptor by PGE(2) triggers a positive feedback loop for its production by up-regulating expression of key components of the PGE(2) biosynthetic cascade (COX-2, mPGES-1 and the EP4 receptor), thus contributing to amplification of BaP1-induced effects in FLSs. These data highlight the importance of FLS as a target for metalloproteases in joint inflammation and provide new insights into the roles of MMPs in inflammatory joint diseases. Moreover, our results may give insights into the importance of the catalytic domain, of MMPs for the inflammatory activity of these enzymes. (AU)

• Processo FAPESP: 09/50896-5 - Estudos dos mecanismos moleculares envolvidos na síntese de prostaglandina E2, induzida pela metaloproteinase BAP1, em fibroblastos sinoviais em cultura, expressão diferencial de genes e das enzimas ciclo-oxigenase-2 e PGE sintase microssomal-1
• Beneficiário: Catarina de Fatima Pereira Teixeira
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 15/50040-4 - Rational approach for searching molecular targets involved in inflammatory events and cell survival
• Beneficiário: Ana Marisa Chudzinski-Tavassi
• Modalidade de apoio: Auxílio à Pesquisa - Programa Centros de Pesquisa em Engenharia
• Processo FAPESP: 08/58988-3 - Estudos dos mecanismos moleculares envolvidos na síntese de prostaglandina E2, induzida pela metaloproteinase BAP1, em fibroblastos sinoviais em cultura: expressão diferencial de genes e das enzimas ciclooxigenase-2 e PGE sintase microssomal-1
• Beneficiário: Cristina Maria Fernandes
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 00/11624-5 - Embriologia de Gastropoda: análise em microscopia de varredura laser confocal
• Beneficiário: Toshie Kawano
• Modalidade de apoio: Auxílio à Pesquisa - Programa Equipamentos Multiusuários