Inatsu Akihito, Kinoshita Manabu, Nakashima Hiroyuki, Shimizu Jun, Saitoh Daizoh, Tamai Seiichi, Seki Shuhji
Department of Laboratory Medicine, National Defense Medical College Hospital, Saitama, Japan.
Hepatology. 2009 Jun;49(6):2044-54. doi: 10.1002/hep.22888.
Although C-reactive protein (CRP) is a representative acute-phase protein produced by hepatocytes, the role of CRP in liver innate immunity remains unclear. Using C57BL/6 mice, the present study investigated how CRP affects the functions of liver macrophages, Kupffer cells, and natural killer / natural killer T (NK/NKT) cells under various conditions, including Escherichia coli infection, septic shock, and multiorgan dysfunction induced by interleukin (IL)-12/lipopolysaccharide (LPS) (generalized Shwartzman reaction [GSR]), and LPS-induced lethal hepatitis in Propionibacterium acnes-primed mice. When mice were challenged with a lethal dose of E. coli, synthetic CRP peptide decreased the mortality without decreasing serum tumor necrosis factor (TNF), presumably by enhancing the phagocytic activity of Kupffer cells. Synthetic CRP greatly decreased the production of TNF and reactive oxygen species from Kupffer cells and thereby rescued mice after lethal LPS challenge. CRP also decreased the mortality from GSR and lethal hepatitis by inhibiting TNF production from Kupffer cells, especially phagocytosing Kupffer cells. However, interferon-gamma production from NK/NKT cells was generally not so affected. CRP reportedly binds to FcgammaRI and FcgammaRII, and the injection of anti-FcgammaRII/III Ab into mice abrogated TNF production from, but increased the phagocytic activity of, Kupffer cells. Furthermore, CRP pretreatment restored the decreased phagocytic activity of Kupffer cells in burn-injured mice and decreased TNF production by Kupffer cells and thereby inhibited mortality after sublethal E. coli infection. If CRP was injected into mice at 1 hour after lethal E. coli challenge, it slightly but significantly increased the survival rate.
CRP thus enhances the phagocytosis of Kupffer cells but decreases their TNF production in a complex manner in which the pathway by way of FcgammaRII may be involved.
尽管C反应蛋白（CRP）是肝细胞产生的一种代表性急性期蛋白，但其在肝脏固有免疫中的作用仍不清楚。本研究使用C57BL/6小鼠，探讨了在各种条件下，包括大肠杆菌感染、脓毒症休克以及由白细胞介素（IL）-12/脂多糖（LPS）诱导的多器官功能障碍（全身性施瓦茨曼反应[GSR]），以及痤疮丙酸杆菌致敏小鼠中LPS诱导的致死性肝炎，CRP如何影响肝脏巨噬细胞、库普弗细胞以及自然杀伤/自然杀伤T（NK/NKT）细胞的功能。当用致死剂量的大肠杆菌攻击小鼠时，合成的CRP肽降低了死亡率，但未降低血清肿瘤坏死因子（TNF），这可能是通过增强库普弗细胞的吞噬活性实现的。合成的CRP大大降低了库普弗细胞TNF和活性氧的产生，从而在致死性LPS攻击后挽救了小鼠。CRP还通过抑制库普弗细胞，尤其是吞噬性库普弗细胞产生TNF，降低了GSR和致死性肝炎的死亡率。然而，NK/NKT细胞产生的干扰素-γ通常未受如此影响。据报道，CRP与FcγRI和FcγRII结合，向小鼠注射抗FcγRII/III抗体可消除库普弗细胞产生TNF，但增加了其吞噬活性。此外，CRP预处理恢复了烧伤小鼠中库普弗细胞降低的吞噬活性，并降低了库普弗细胞产生TNF，从而抑制了亚致死性大肠杆菌感染后的死亡率。如果在致死性大肠杆菌攻击后1小时向小鼠注射CRP，可轻微但显著提高存活率。
因此，CRP以一种可能涉及FcγRII途径的复杂方式增强了库普弗细胞的吞噬作用，但降低了其TNF的产生。
