Zimecki Michał, Chodaczek Grzegorz, Kocieba Maja, Kruzel Marian L
Department of Experimental Therapy, Institute of Immunology and Experimental Therapy of the Polish Academy of Sciences, Weigla 12, 53-114 Wroclaw, Poland.
FEMS Immunol Med Microbiol. 2004 Oct 1;42(2):167-72. doi: 10.1016/j.femsim.2004.04.003.
C3H/HeCr mice are more susceptible to infection compared with other strains. Lactoferrin (LF), a protein involved in innate defense, was shown to protect mice against lethal endotoxemia. In this investigation we attempt to explain the cause of increased susceptibility of C3H/HeCr mice to LPS and lack of protective LF action in these mice. We found that C3H/HeCr mice produced up to 5-fold more serum TNFalpha and 66% higher IFNgamma levels in response to i.v. LPS injection than the control, CBA strain. 24 h pretreatment of C3H/HeCr mice with LF did not cause inhibition of the LPS-induced TNFalpha serum levels, whereas in CBA mice LF significantly decreased TNFalpha level. IL-6 serum levels, in turn, were lowered in C3H/HeCr mice but elevated in CBA mice. That differential regulation of cytokine production by LF in C3H/HeCr mice paralleled a decreased survival after lethal LPS injection - 10% vs. 60% in control, PBS treated mice. In addition, determination of colony forming units (CFU) in livers and spleens after administration of 10(8) Escherichia coli revealed that pretreatment of CBA mice with LF caused a marked reduction of CFU in these organs, whereas in C3H/HeCr mice the changes were insignificant. These results indicate that the altered TNFalpha/IL-6 ratio in C3H/HeCr mice, as compared to control CBA mice, as well as the increased IFNgamma level, may be responsible for the increased susceptibility to endotoxemia in that substrain. We also suggest that an association exists between the LF protective effect against endotoxic sequelae and the insult-induced systemic immune response.
与其他品系相比，C3H/HeCr小鼠更容易受到感染。乳铁蛋白（LF）是一种参与天然防御的蛋白质，已被证明能保护小鼠免受致死性内毒素血症的侵害。在本研究中，我们试图解释C3H/HeCr小鼠对脂多糖（LPS）易感性增加以及这些小鼠缺乏LF保护作用的原因。我们发现，静脉注射LPS后，C3H/HeCr小鼠产生的血清肿瘤坏死因子α（TNFα）比对照CBA品系多5倍，干扰素γ（IFNγ）水平高66%。用LF对C3H/HeCr小鼠进行24小时预处理，并未抑制LPS诱导的血清TNFα水平，而在CBA小鼠中，LF显著降低了TNFα水平。相反，C3H/HeCr小鼠的白细胞介素6（IL-6）血清水平降低，而CBA小鼠的IL-6血清水平升高。LF对C3H/HeCr小鼠细胞因子产生的这种差异调节与致死性LPS注射后存活率降低相平行——在对照的经磷酸盐缓冲液（PBS）处理的小鼠中为60%，而在C3H/HeCr小鼠中为10%。此外，在给予10⁸大肠杆菌后测定肝脏和脾脏中的菌落形成单位（CFU），结果显示用LF对CBA小鼠进行预处理可使这些器官中的CFU显著减少，而在C3H/HeCr小鼠中，变化不显著。这些结果表明，与对照CBA小鼠相比，C3H/HeCr小鼠中TNFα/IL-6比值的改变以及IFNγ水平的升高，可能是该亚品系对内毒素血症易感性增加的原因。我们还认为，LF对内毒素后遗症的保护作用与损伤诱导的全身免疫反应之间存在关联。
