1. INTRODUÇÃO
6.6 Expressão de citocinas
As células de Paneth expressam de maneira constitutiva o gene para TNF-alfa, e embora o RNA fosse facilmente encontrado, a proteína não era expressa devido a um mecanismo regulatório pós-transcripcional ( KESHAV et al., 1990) (CHEN; SHYU, 1995)(Keshav, 2006) ). Se essa produção de TNF-alfa é em resposta a agressão ainda não está perfeitamente esclarecido.
Liboni e colaboradores (2005), em um trabalho utilizando células de linhagens H4 (que simulam enterócitos imaturos) e células Caco-2 (que simulam enterócitos maduros) mostram que a produção de IL-8 estava aumentada quando estas células eram deprivadas de glutamina por 24 horas e que estas reagiam de maneira exacerbada quando expostas ao LPS e quando comparadas com os controles com glutamina. Outra informação interessante era que os enterócitos imaturos eram mais sensíveis a esta estimulação que os mais diferenciados.
Coëffier e colaboradores (2001), em trabalho utilizando biópsia de jejuno de voluntários saudáveis, constataram que a concentração de IL-8 era menor naqueles que recebiam uma solução com glutamina e tinha seus fragmentos cultivados em meio com glutamina do que aqueles fragmentos provenientes de voluntários que recebiam salina e tinham seus fragmentos cultivados em meio sem glutamina. Essa diferença também foi observada em amostras de voluntários que receberam salina e tiveram seus fragmentos cultivados em meio com glutamina quando comparadas com aqueles cultivados em meio sem glutamina. O estudo não detectou IL-1ß e TNF-α em níveis suficientes para realizar análises estatísticas, mas não detectou alterações nos níveis de mRNA para IL-1ß, TNF-α e IL-8 nos fragmentos de biópsia de voluntários que receberam ou não glutamina, sugerindo um provável mecanismo regulatório pós-trancrição para pelo menos IL-8.
Coëffier e colaboradores (2003), em um outro trabalho utilizando biópsia de duodeno de voluntários saudáveis cultivados em cultura, observaram que IL-1ß (dose de 2ng/mL) estimulava a produção de IL-6 e IL-8, mas não afetava a produção de IL-4 e 10 e que em concentrações crescentes de glutamina (0,5-10mM) reduzia a produção de IL-6 e 8, enquanto aumentava a produção de IL-10 (doses mais altas de glutamina aumentavam a expressão de RNAm para IL-10, mas o aumento da proteína só foi detectado após estimulação com IL-1ß). Novamente não houve diferenças nos transcritos para IL-8 e TNF-α não foi detectado nas amostras
7 CONCLUSÃO
A importância da glutamina como combustível para os enterócitos já é conhecida, mas o seu papel sobre as outras linhagens do epitélio intestinal ainda não foi bem estudado. Parte disso se deve ao fato de que, isoladamente, o epitélio intestinal não havia sido bem reproduzido in vitro. O cultivo de células diferenciadas requeria a administração exógena de fatores de crescimento especifico para cada tipo de linhagem celular que se desejasse estudar. O modelo de organoide intestinal é capaz de gerar um epitélio intestinal contendo as principais linhagens celulares (células de Paneth, caliciformes, enteroendócrinas e enterócitos) de maneira em que estas mantém a produção de seus produtos específicos e posição relativa à estrutura vilo-cripta de maneira semelhante a observada in vivo, possuindo inclusive alguns elementos do sistema imune inato responsáveis pela responsividade ao LPS (TLR4 e MD-2), algo que outros modelos in vitro não possuem de maneira completa.
Quanto ao efeito da privação de glutamina sobre as células secretoras do epitélio, aquela parece possuir ação regulatória sobre as células de Paneth, visto que as maiores diferenças observadas são em produtos dessa linhagem celular em meio privado de glutamina, tais como:
• Redução da transcrição de lisozima.
• Redução da transcrição de MD-2, a proteína acessória do TLR4.
• Redução da transcrição de TNF-α, encontrada constitutivamente nessas células.
Mais estudos são necessários para o melhor entendimento do papel da glutamina nessas células e o modelo de enteroides parece ser o ideal para esses estudos, pois apresenta um epitélio diferenciado e consegue prover uma arquitetura vilo-cripta semelhante a observada in vivo.
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