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A snake venom group IIA PLA₂ with immunomodulatory activity induces formation of lipid droplets containing 15-d-PGJ₂ in macrophages.

ABSTRACT: Crotoxin B (CB) is a catalytically active group IIA sPLA₂ from Crotalus durissus terrificus snake venom. In contrast to most GIIA sPLA₂s, CB exhibits anti-inflammatory effects, including the ability to inhibit leukocyte functions. Lipid droplets (LDs) are lipid-rich organelles associated with inflammation and recognized as a site for the synthesis of inflammatory lipid mediators. Here, the ability of CB to induce formation of LDs and the mechanisms involved in this effect were investigated in isolated macrophages. The profile of CB-induced 15-d-PGJ₂ (15-Deoxy-Delta-12,14-prostaglandin J₂) production and involvement of LDs in 15-d-PGJ₂ biosynthesis were also investigated. Stimulation of murine macrophages with CB induced increased number of LDs and release of 15-d-PGJ₂. LDs induced by CB were associated to PLIN2 recruitment and expression and required activation of PKC, PI3K, MEK1/2, JNK, iPLA₂ and PLD. Both 15-d-PGJ₂ and COX-1 were found in CB-induced LDs indicating that LDs contribute to the inhibitory effects of CB by acting as platform for synthesis of 15-d-PGJ₂, a pro-resolving lipid mediator. Together, our data indicate that an immunomodulatory GIIA sPLA₂ can directly induce LD formation and production of a pro-resolving mediator in an inflammatory cell and afford new insights into the roles of LDs in resolution of inflammatory processes.

SUBMITTER: Giannotti KC

PROVIDER: S-EPMC5481388 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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A snake venom group IIA PLA2 with immunomodulatory activity induces formation of lipid droplets containing 15-d-PGJ2 in macrophages.

Giannotti Karina Cristina KC Leiguez Elbio E Carvalho Ana Eduarda Zulim de AEZ Nascimento Neide Galvão NG Matsubara Márcio Hideki MH Fortes-Dias Consuelo Latorre CL Moreira Vanessa V Teixeira Catarina C

Scientific reports 20170622 1

Crotoxin B (CB) is a catalytically active group IIA sPLA2 from Crotalus durissus terrificus snake venom. In contrast to most GIIA sPLA2s, CB exhibits anti-inflammatory effects, including the ability to inhibit leukocyte functions. Lipid droplets (LDs) are lipid-rich organelles associated with inflammation and recognized as a site for the synthesis of inflammatory lipid mediators. Here, the ability of CB to induce formation of LDs and the mechanisms involved in this effect w ...[more]

PMID: 28642580

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Project description:BackgroundEndogenous phospholipases A2 (PLA2) play a fundamental role in inflammation, neurodegenerative diseases, apoptosis and cellular senescence. Neurotoxins with PLA2 activity are found in snake venoms from the Elapidae and Viperidae families. The mechanism of action of these neurotoxins have been studied using hippocampal and cerebellar neuronal cultures showing [Ca2+]i increase, mitochondrial depolarization and cell death. Astrocytes are rarely used as a model, despite being modulators at the synapses and responsible for homeostasis and defense in the central nervous system. Preserving the cell division ability, they can be utilized to study the cell proliferation process. In the present work cultured astrocytes and glioblastoma cells were employed to characterize the action of β-micrustoxin (previously named Mlx-9), a PLA2 isolated from Micrurus lemniscatus snake venom. The β-micrustoxin structure was determined and the cell proliferation, cell cycle phases and the regulatory proteins p53, p21 and p27 were investigated.Methodsβ-micrustoxin was characterized biochemically by a proteomic approach. Astrocytes were obtained by dissociation of pineal glands from Wistar rats; glioblastoma tumor cells were purchased from ATCC and Sigma and cultured in DMEM medium. Cell viability was evaluated by MTT assay; cell proliferation and cell cycle phases were analyzed by flow cytometry; p53, p21 and p27 proteins were studied by western blotting and immunocytochemistry.ResultsProteomic analysis revealed fragments on β-micrustoxin that aligned with a PLA2 from Micrurus lemniscatus lemniscatus previously identified as transcript ID DN112835_C3_g9_i1/m.9019. β-micrustoxin impaired the viability of astrocytes and glioblastoma tumor cells. There was a reduction in cell proliferation, an increase in G2/M phase and activation of p53, p21 and p27 proteins in astrocytes.ConclusionThese findings indicate that β-micrustoxin from Micrurus lemniscatus venom could inhibit cell proliferation through p53, p21 and p27 activation thus imposing cell cycle arrest at the checkpoint G2/M.

Dataset Information

A snake venom group IIA PLA₂ with immunomodulatory activity induces formation of lipid droplets containing 15-d-PGJ₂ in macrophages.

Publications

A snake venom group IIA PLA<sub>2</sub> with immunomodulatory activity induces formation of lipid droplets containing 15-d-PGJ<sub>2</sub> in macrophages.

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