Toll-like receptor 4 mediates alcohol-induced steatohepatitis through bone marrow-derived and endogenous liver cells in mice.
Toll-like receptor 4 mediates alcohol-induced steatohepatitis through bone marrow-derived and endogenous liver cells in mice.
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DOI：
10.1111/j.1530-0277.2011.01487.x
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发表时间：
2011-08
期刊：
影响因子：
--
通讯作者：
Seki E
中科院分区：
文献类型：
--
作者：
Inokuchi S;Tsukamoto H;Park E;Liu ZX;Brenner DA;Seki E
过量的酒精摄入导致肠通透性增加，从而诱导肠源性脂多糖（LPS）移位至门静脉。门静脉中增加的LPS通过肝脏中的Toll样受体（TLR）4刺激枯否细胞。Kupffer细胞中激活的TLR 4信号诱导多种炎症介质，包括TNF-α、IL-1β和活性氧，导致肝损伤。肝星状细胞（HSC）也表达TLR 4。本研究调查了骨髓（BM）衍生细胞（包括枯否细胞）或非BM衍生内源性肝细胞（包括HSC）上的TLR 4是否有助于小鼠酒精诱导的脂肪性肝炎和纤维化的进展。TLR 4 BM嵌合体（野生型（WT）小鼠与TLR 4-/- BM或TLR 4-/-小鼠与WT BM）通过脂质体氯膦酸盐注射与全身照射和BM移植（BMT）的组合产生，随后用胃内酒精喂养处理。移植WT BM的WT小鼠表现出肝损伤、脂肪变性、炎症和纤维化反应。相反，具有TLR 4-/- BM的TLR 4-/-小鼠显示较少的脂肪变性、肝损伤和炎症。值得注意的是，两种TLR 4嵌合小鼠中的脂肪变性、巨噬细胞浸润和ALT水平显示出移植有WT BM的WT小鼠和移植有TLR 4-/- BM的TLR 4-/-小鼠之间的中间水平。在携带WT BM的WT小鼠中，肝纤维化标志物（胶原α1（I）、TIMP 1、TGF-β1）和炎性细胞因子（IL-1β、IL-6）的mRNA表达显著增加，但在TLR 4嵌合小鼠和移植TLR 4-/- BM的TLR 4-/-小鼠中增加较少。BM衍生和非BM衍生肝细胞中的TLR 4信号传导是慢性酒精治疗后肝脂肪变性、炎症和纤维化反应所必需的。
Excessive alcohol intake causes an increase in intestinal permeability that induces translocation of gut-derived lipopolysaccharide (LPS) to the portal vein. Increased LPS in the portal vein stimulates Kupffer cells through Toll-like receptor (TLR) 4 in the liver. Activated TLR4 signaling in Kupffer cells induces various inflammatory mediators including TNF-α, IL-1β and reactive oxygen species, resulting in liver injury. Hepatic stellate cells (HSCs) also express TLR4. This study investigates whether TLR4 on bone marrow (BM)-derived cells, including Kupffer cells, or non-BM-derived endogenous liver cells, including HSCs, contributes to the progression of alcohol-induced steatohepatitis and fibrogenesis in mice. TLR4 BM chimera (wild type (WT) mice with TLR4-/- BM or TLR4-/- mice with WT BM) were generated by the combination of liposomal clodronate injection with whole body irradiation and BM transplantation (BMT), followed by treatment with intragastric alcohol feeding. WT mice transplanted with WT BM exhibited liver injury, steatosis, inflammation and a fibrogenic response. Conversely, TLR4-/- mice with TLR4-/- BM displayed less steatosis, liver injury and inflammation. Notably, steatosis, macrophage infiltration and ALT levels in both TLR4 chimeric mice showed intermediate levels between WT mice transplanted with WT BM and TLR4-/- mice transplanted with TLR4-/- BM. Hepatic mRNA expression of fibrogenic markers (collagen α1(I), TIMP1, TGF-β1) and inflammatory cytokines (IL-1β, IL-6) were markedly increased in WT mice with WT BM, but there was less of an increase in both TLR4-chimeric mice and in TLR4-/- mice transplanted with TLR4-/- BM. TLR4 signaling in both BM-derived and non-BM-derived liver cells is required for liver steatosis, inflammation, and a fibrogenic response after chronic alcohol treatment.
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影响因子：
29.4
作者：
Miura K;Kodama Y;Inokuchi S;Schnabl B;Aoyama T;Ohnishi H;Olefsky JM;Brenner DA;Seki E
通讯作者：
Seki E
DOI：
10.1002/hep.22470
发表时间：
2008-10
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Hritz I;Mandrekar P;Velayudham A;Catalano D;Dolganiuc A;Kodys K;Kurt-Jones E;Szabo G
通讯作者：
Szabo G
影响因子：
15.9
作者：
TSUKAMOTO, H;HORNE, W;BRITTENHAM, GM
通讯作者：
BRITTENHAM, GM
影响因子：
4.3
作者：
Szabo, Gyongyi;Bala, Shashi
通讯作者：
Bala, Shashi
DOI：
10.1111/j.1440-1746.2006.04650.x
发表时间：
2007-06-01
影响因子：
4.1
作者：
Thakur, Varsha;McMullen, Megan R.;Nagy, Laura E.
通讯作者：
Nagy, Laura E.