Host Defense Against Infection and Dietary Fatty Acids

描述(由申请人提供)：已知膳食脂肪酸可调节免疫防御系统。然而，这种调节的潜在机制还没有被很好地理解。我们前期的研究结果表明，饱和脂肪酸激活Toll样受体(TLRs)，导致NFkappaB激活，并导致巨噬细胞表达丝裂原诱导的环氧合酶(COX-2)。然而，所有被测试的不饱和脂肪酸都能抑制饱和脂肪酸或细菌脂多糖(LPS)诱导的TLR激活。与n-6多不饱和脂肪酸相比，n-3多不饱和脂肪酸优先抑制TLR介导的信号通路的激活和巨噬细胞靶基因的表达。这些结果证明了脂肪酸调节受体介导的信号通路和靶基因表达的新机制，并表明TLR介导的靶基因表达和免疫反应可以受到不同类型的膳食脂肪酸的调节。下一个问题是这种调制的功能后果是什么。TLRs在识别入侵的微生物病原体和诱导先天和获得性免疫反应以消除感染微生物方面发挥着重要作用。作为我们先前研究的合乎逻辑的延伸，我们建议在这里确定饮食脂肪酸组成的变化是否可以改变免疫反应和随后的宿主对感染的防御，并阐明脂肪酸调节感染诱导的先天性和获得性免疫反应的机制。其具体目的是：1)确定饱和脂肪酸激活TLR4和TLR2二聚体的机制，而多不饱和脂肪酸抑制这种激活。2)确定受饱和和多不饱和脂肪酸差异调控的靶基因；3)利用动物模型确定饱和和不饱和脂肪酸是否由于调节TLR信号通路和靶基因表达而改变免疫反应；4)在动物模型中确定饮食脂肪酸类型是否改变宿主对细菌感染的易感性。这些研究的结果将提供一个全面的图景，说明不同类型的脂肪酸如何调节TLR衍生的信号通路和靶基因的表达，从而导致不同的免疫反应和宿主对入侵微生物病原体的防御。此外，从这些研究中获得的机械性信息将加强我们对感染如何增加患某些慢性病的风险以及如何通过饮食手段降低此类风险的理解。

DESCRIPTION (provided by applicant): Dietary fatty acids are known to modulate immunological defense systems. However, underlying mechanisms for such modulation are not well understood. Results from our previous studies demonstrated that saturated fatty acids activate Toll-like receptors (TLRs) leading to NFkappaB activation and the expression of mitogen inducible cyclooxygenase (COX-2) in macrophages. However, all unsaturated fatty acids tested inhibit TLR activation induced by saturated fatty acids or bacterial lipopolysaccharide (LPS). N-3 polyunsaturated fatty acids (PUFAs) as compared with n-6 PUFAs preferentially inhibit the activation of TLRmediated signaling pathways and target gene expression in macrophages. These results document novel mechanism by which fatty acids modulate receptor-mediated signaling pathways and target gene expression, and suggest that TLR-mediated target gene expression and immune responses can be modulated by types of dietary fatty acids. The next question is what the functional consequence of this modulation is. TLRs play a major role in recognition of invading microbial pathogens and induction of innate and adaptive immune responses for elimination of infecting microbes. As a logical extension of our previous studies, we propose here to determine whether changes in the dietary fatty acid composition can alter immune responses and subsequent host defense against infection, and to elucidate the mechanisms by which fatty acids modulate infection-induced innate and adaptive immune responses. The specific aims are: 1) To determine mechanisms by which saturated fatty acids activate TLR4 and TLR2 dimers, but polyunsaturated fatty acids inhibit the activation. 2) To identify target genes that are differentially regulated by saturated and polyunsaturated fatty acids; 3) To determine whether saturated and unsaturated fatty acids alter immune responses as a result of modulation of TLR-signaling pathways and target gene expression using animal models; 4) To determine whether types of dietary fatty acids alter susceptibility of the host to bacterial infection in animal models. Results from proposed studies will provide a comprehensive picture as to how the modulation of TLR-derived signaling pathways and target gene expression by different types of fatty acids leads to differential immune responses and host defense against the invading microbial pathogens. In addition, the mechanistic information gained from these studies will enhance our understanding as to how infections can increase risks of developing certain chronic diseases and how such risks can be reduced by dietary means.