title: PPAR-γ activation by Tityus serrulatus venom regulates lipid body formation and lipid mediator production.
abstract: Tityus serrulatus venom (TsV) consists of numerous peptides with different physiological and pharmacological activities. Studies have shown that scorpion venom increases pro-inflammatory cytokine production, contributing to immunological imbalance, multiple organ dysfunction, and patient death. We have previously demonstrated that TsV is a venom-associated molecular pattern (VAMP) recognized by TLRs inducing intense inflammatory reaction through the production of pro-inflammatory cytokines and arachidonic acid-derived lipid mediators prostaglandin (PG)E2 and leukotriene (LT)B4. Lipid bodies (LBs) are potential sites for eicosanoid production by inflammatory cells. Moreover, recent studies have shown that the peroxisome proliferator-activated receptor gamma (PPAR-γ) is implicated in LB formation and acts as an important modulator of lipid metabolism during inflammation. In this study, we used murine macrophages to evaluate whether the LB formation induced by TsV after TLR recognition correlates with lipid mediator generation by macrophages and if it occurs through PPAR-γ activation. We demonstrate that TsV acts through TLR2 and TLR4 stimulation and PPAR-γ activation to induce LB formation and generation of PGE2 and LTB4. Our data also show that PPAR-γ negatively regulates the pro-inflammatory NF-κB transcription factor. Based on these results, we suggest that during envenomation, LBs constitute functional organelles for lipid mediator production through signaling pathways that depend on cell surface and nuclear receptors. These findings point to the inflammatory mechanisms that might also be triggered during human envenomation by TsV.
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Brazil. Electronic address: karina_zoccal4@hotmail.com.
authors.forename: Karina Furlani
authors.initials: KF
authors.lastname: Zoccal
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Brazil. Electronic address: francisogarcia@usp.br.
authors.forename: Francisco Wanderley Garcia
authors.initials: FW
authors.lastname: Paula-Silva
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Brazil. Electronic address: claubitencourt@yahoo.com.
authors.forename: Claudia da Silva
authors.initials: Cda S
authors.lastname: Bitencourt
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Brazil. Electronic address: sorgi@fcfrp.usp.br.
authors.forename: Carlos Artério
authors.initials: CA
authors.lastname: Sorgi
authors.affiliation: Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Brazil. Electronic address: karla@fcfrp.usp.br.
authors.forename: Karla de Castro Figueiredo
authors.initials: Kde C
authors.lastname: Bordon
authors.affiliation: Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Brazil. Electronic address: ecabraga@fcfrp.usp.br.
authors.forename: Eliane Candiani
authors.initials: EC
authors.lastname: Arantes
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Brazil. Electronic address: faccioli@fcfrp.usp.br.
authors.forename: Lúcia Helena
authors.initials: LH
authors.lastname: Faccioli
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D016207:Cytokines / Q000276:immunology; D015232:Dinoprostone / Q000276:immunology; D006801:Humans; D007975:Leukotriene B4 / Q000276:immunology; D066292:Lipid Droplets / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B; D047495:PPAR gamma / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D065008:Scorpion Stings / Q000276:immunology* / Q000378:metabolism; D012604:Scorpion Venoms / Q000633:toxicity*; D012605:Scorpions; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D047495:PPAR gamma; D012604:Scorpion Venoms; D007975:Leukotriene B4; D015232:Dinoprostone
keywords: Leukotrienes; Lipid bodies; Peroxisome proliferator-activated receptor gamma; Prostaglandins; Tityus serrulatus venom; Toll-like receptors