Avaliação ex vivo da expressão de TLR-2 e TLR-4 em leucócitos de equinos e sua relação com a tolerância à endotoxina
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Data
2009-07-28
Autores
Carrenho, Luciana Cristina de Andrade [UNESP]
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
A endotoxemia é um importante distúrbio sistêmico que se origina da resposta do hospedeiro a um componente das bactérias Gram-negativas, o lipopolissacarídeo (LPS) ou endotoxina, que é liberado após bacteriólise ou rápida multiplicação. A ativação do sistema imune inato pelo LPS é um fator chave para o disparo da resposta inflamatória pelo hospedeiro e que acarreta a produção de mediadores inflamatórios, responsáveis pelos eventos patológicos da endotoxemia. A interação dos receptores Toll-like (TLRs) com antígenos específicos deflagram a resposta inflamatória, sendo que o receptor Toll-like-4 (TLR-4) é ativado pela ação das endotoxinas, enquanto o receptor Toll-like-2 (TLR-2) interage com uma variedade de componentes microbianos. Uma exposição prévia a baixas concentrações de LPS pode tornar os cavalos “tolerantes” a um desafio letal subsequente, acarretando uma diminuição na produção de citocinas inflamatórias por um período transitório. Pouco se sabe a respeito do mecanismo celular deste fenômeno em equinos, supondo-se o envolvimento dos receptores Toll-like semelhante ao encontrado em outras espécies. Com este estudo investigaram-se os mecanismos celulares da tolerância à endotoxina em um modelo ex vivo com sangue total. Foi demonstrado redução na síntese de citocinas pró-inflamatórias (TNF-α, IL-1 e IL-6), aumento da expressão gênica da citocina anti-inflamatória IL-10, e ausência de expressão do TGF-β, após o desafio secundário com LPS. A maior expressão dos receptores TLR-2 e -4 após o segundo estímulo de LPS demonstrou que a tolerância à endotoxina não acarreta diminuição da expressão de ambos os receptores em equinos.
Endotoxemia is an important systemic disease originated from host response to a component of Gram-negative bacteria, lipopolysaccharide (LPS) or endotoxin, which is released after bacteria death or quick replication. The innate immune recognition of LPS has a key role triggering host inflammatory answer and is due to inflammatory mediator’s synthesis, which are responsible for pathologic events of endotoxemia. Signs initiated by interaction of Toll-like receptors (TLRs) with specific products induce the inflammatory response. Toll-like receptor-4 (TLR- 4) is activated by endotoxin action while Toll-like receptor-2 (TLR-2) interacts with a range of microbial compounds. Some studies demonstrate that both can act like LPS receptors, although by independent pathways. It was demonstrated that a previous exposition to low concentrations of LPS can render horses “tolerant” to a lethal subsequent challenge with endotoxin, leading to a diminished release of inflammatory cytokines during a transient period. However, little is known about the cellular mechanisms involved in this phenomenon in horses, suspecting that there is involvement of cell surface receptors, similarly to other species. This study investigated cellular mechanisms of endotoxin tolerance in a whole blood ex vivo model, demonstrating a reduction on pro-inflammatory cytokines synthesis (TNF- α, IL-1 and IL-6), increased gene expression of anti-inflammatory cytokine IL-10 and no alteration in TGF-β expression, after a secondary stimulus with LPS. The Toll-like receptors-2 and -4 increased expression after a second stimulus with LPS showed that endotoxin tolerance does not lead to a decreased expression of both receptors in horses.
Endotoxemia is an important systemic disease originated from host response to a component of Gram-negative bacteria, lipopolysaccharide (LPS) or endotoxin, which is released after bacteria death or quick replication. The innate immune recognition of LPS has a key role triggering host inflammatory answer and is due to inflammatory mediator’s synthesis, which are responsible for pathologic events of endotoxemia. Signs initiated by interaction of Toll-like receptors (TLRs) with specific products induce the inflammatory response. Toll-like receptor-4 (TLR- 4) is activated by endotoxin action while Toll-like receptor-2 (TLR-2) interacts with a range of microbial compounds. Some studies demonstrate that both can act like LPS receptors, although by independent pathways. It was demonstrated that a previous exposition to low concentrations of LPS can render horses “tolerant” to a lethal subsequent challenge with endotoxin, leading to a diminished release of inflammatory cytokines during a transient period. However, little is known about the cellular mechanisms involved in this phenomenon in horses, suspecting that there is involvement of cell surface receptors, similarly to other species. This study investigated cellular mechanisms of endotoxin tolerance in a whole blood ex vivo model, demonstrating a reduction on pro-inflammatory cytokines synthesis (TNF- α, IL-1 and IL-6), increased gene expression of anti-inflammatory cytokine IL-10 and no alteration in TGF-β expression, after a secondary stimulus with LPS. The Toll-like receptors-2 and -4 increased expression after a second stimulus with LPS showed that endotoxin tolerance does not lead to a decreased expression of both receptors in horses.
Descrição
Palavras-chave
Cavalo, Equino, Endotoxemia, Cavalos, Receptores Toll-Like, Citocinas, Receptor 2 Toll-Like, Receptor 4 Toll-Like, Horses, Toll-Like Receptors, Cytokines, Endotoxemia
Como citar
CARRENHO, Luciana Cristina de Andrade. Avaliação ex vivo da expressão de TLR-2 e TLR-4 em leucócitos de equinos e sua relação com a tolerância à endotoxina. 2009. 72 f. Dissertação (mestrado) - Universidade Estadual Paulista, Faculdade de Odontologia e Curso de Medicina Veterinária, 2009.