title: Melatonin attenuates the TLR4-mediated inflammatory response through MyD88- and TRIF-dependent signaling pathways in an in vivo model of ovarian cancer.
abstract: 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 μg of 7,12-dimethylbenz(a)anthracene (DMBA) dissolved in 10 μL 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 μg/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 (IkBα), IkB kinase alpha (IKK-α), TNF receptor-associated factor 6 (TRAF6), TRIF, interferon regulatory factor 3 (IRF3), interferon β (IFN-β), tumor necrosis factor alpha (TNF-α), and interleukin (IL)-6. In addition, mel significantly attenuated the expression of IkBα, NFkB p65, TRIF and IRF-3, which are involved in TLR4-mediated signaling in OC during ethanol intake.
  
  
  CONCLUSIONS
  Collectively, our results suggest that mel attenuates the TLR4-induced MyD88- and TRIF-dependent signaling pathways in ethanol-preferring rats with OC.
authors: Department of Anatomy, Institute of Biosciences, UNESP - Universidade Estadual Paulista, Botucatu, SP, Brazil. guchuffa@yahoo.com.br.
authors: Luiz Gustavo A
authors: LG
authors: Chuffa
authors: Department of Anatomy, Institute of Biosciences, UNESP - Universidade Estadual Paulista, Botucatu, SP, Brazil. bialogia@gmail.com.
authors: Beatriz A
authors: BA
authors: Fioruci-Fontanelli
authors: Department of Anatomy, Institute of Biosciences, UNESP - Universidade Estadual Paulista, Botucatu, SP, Brazil. mendeslm@ig.com.br.
authors: Leonardo O
authors: LO
authors: Mendes
authors: Institute of Biology, State University of North of Parana, UENP - Campus Luiz Meneghel, Bandeirantes, PR, Brazil. fabioseiva@msn.com.
authors: Fábio R
authors: FR
authors: Ferreira Seiva
authors: Department of Morphology and Pathology, UFSCar - Universidade Federal de São Carlos, São Carlos, SP, Brazil. martinez@ufscar.br.
authors: Marcelo
authors: M
authors: Martinez
authors: Department of Anatomy, Cell Biology and Physiology and Biophysics, UNICAMP - Universidade de Campinas, Campinas, SP, Brazil. wjfavaro@unicamp.br.
authors: Wagner J
authors: WJ
authors: Fávaro
authors: Department of Anatomy, Institute of Biosciences, UNESP - Universidade Estadual Paulista, Botucatu, SP, Brazil. domeniconi@ibb.unesp.br.
authors: Raquel F
authors: RF
authors: Domeniconi
authors: Department of Anatomy, Institute of Biosciences, UNESP - Universidade Estadual Paulista, Botucatu, SP, Brazil. pinheiro@ibb.unesp.br.
authors: Patrícia F F
authors: PF
authors: Pinheiro
authors: Center for the Study of Venoms and Venomous Animals (CEVAP), UNESP - Univ Estadual Paulista, Botucatu, SP, Brazil. luci@cevap.org.br.
authors: Lucilene
authors: L
authors: Delazari Dos Santos
authors: Department of Morphology and Pathology, UFSCar - Universidade Federal de São Carlos, São Carlos, SP, Brazil. martinez@ibb.unesp.br.
authors: Francisco Eduardo
authors: FE
authors: Martinez
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D008550:Melatonin / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; D018836:Inflammation Mediators; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C470409:TICAM1 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D008550:Melatonin
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