Melatonin attenuates the TLR4-mediated inflammatory response through MyD88-and TRIF-dependent signaling pathways in an in vivo model of ovarian cancer

Background: Toll-like receptors (TLRs) are effector molecules expressed on the surface of ovarian cancer (OC) cells, but the functions of the TLR2/TLR4 signaling pathways in these cells remain unclear. Melatonin (mel) acts as an anti-inflammatory factor and has been reported to modulate TLRs in some...

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Bibliographic Details
Authors: Chuffa, Luiz Gustavo de Almeida [UNESP], Fioruci-Fontanelli, Beatriz Aparecida [UNESP], Mendes, Leonardo de Oliveira [UNESP], Seiva, Fábio Rodrigues Ferreira, Martinez, Marcelo, Favaro, Wagner José, Domeniconi, Raquel Fantin [UNESP], Pinheiro, Patricia Fernanda Felipe [UNESP], Santos, Lucilene Delazari dos [UNESP], Martinez, Francisco Eduardo
Format: article
Status:Published version
Publication Date:2015
Country:Brasil
Institution:Universidade Estadual Paulista (UNESP)
Repository:Repositório Institucional da UNESP
Language:English
OAI Identifier:oai:repositorio.unesp.br:11449/128549
Online Access:http://www.biomedcentral.com/1471-2407/15/34
http://hdl.handle.net/11449/128549
Access Level:Open access
Keyword:Ovarian cancer
Melatonin
Inflammation
TLR4
MyD88
TRIF
Description
Summary:Background: Toll-like receptors (TLRs) are effector molecules expressed on the surface of ovarian cancer (OC) cells, but the functions of the TLR2/TLR4 signaling pathways in these cells remain unclear. Melatonin (mel) acts as an anti-inflammatory factor and has been reported to modulate TLRs in some aggressive tumor cell types. Therefore, we investigated OC and the effect of long-term mel therapy on the signaling pathways mediated by TLR2 and TLR4 via myeloid differentiation factor 88 (MyD88) and toll-like receptor-associated activator of interferon (TRIF) in an ethanol-preferring rat model.Methods: To induce OC, the left ovary of animals either consuming 10% (v/v) ethanol or not was injected directly under the bursa with a single dose of 100 mu g of 7,12-dimethylbenz(a) anthracene (DMBA) dissolved in 10 mu L of sesame oil. The right ovaries were used as sham-surgery controls. After developing OC, half of the animals received i.p. injections of mel (200 mu g/100 g b.w./day) for 60 days.Results: Although mel therapy was unable to reduce TLR2 levels, it was able to suppress the OC-associated increase in the levels of the following proteins: TLR4, MyD88, nuclear factor kappa B (NFkB p65), inhibitor of NFkB alpha (IkB alpha), IkB kinase alpha (IKK-alpha), TNF receptor-associated factor 6 (TRAF6), TRIF, interferon regulatory factor 3 (IRF3), interferon beta (IFN-beta), tumor necrosis factor alpha (TNF-alpha), and interleukin (IL)-6. In addition, mel significantly attenuated the expression of IkB alpha, NFkB p65, TRIF and IRF-3, which are involved in TLR4-mediated signaling in OC during ethanol intake.Conclusion: Collectively, our results suggest that mel attenuates the TLR4-induced MyD88- and TRIF-dependent signaling pathways in ethanol-preferring rats with OC.

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