Kostense S, Sun W H, Cottey R, Taylor S F, Harmeling S, Zander D, Small P A, Bender B S
Department of Pathology and Laboratory Medicine, University of Florida College of Medicine, Gainesville 32610-0275, USA.
Antiviral Res. 1998 May;38(2):117-30. doi: 10.1016/s0166-3542(98)00019-9.
Interleukin 12 (IL-12) directs the differentiation of undifferentiated T helper (Th0) cells to T helper type 1 (Th1) cells and induces a cell-mediated immune response. To evaluate the effect of IL-12 on the course of influenza A virus infection, BALB/c mice were administered a daily intraperitoneal dose of 1000 ng of IL-12 or saline on days -1 to +4 for a total of six treatments. The treatment generally enhanced Th1-mediated responses. IFNgamma lung concentrations were 1193 +/- 275 pg/100 microl in controls and 3693 +/- 745 pg/100 microl in IL-12-treated mice at day 5. IFNgamma levels were undetectable at day 13 in controls and 1335 +/- 220 pg/100 microl in IL-12-treated mice. Cytokine production was also assessed at the single-cell level for mediastinal lymph nodes. IL-12 treatment increased the number of IL-2- and IFNgamma-producing cells and decreased the number of IL-4- and IL-10-producing cells. IL-12 treatment decreased the anti-influenza antibody response, especially anti-influenza IgG1 antibody resulting in an increased IgG2a/IgG1 ratio. Primary pulmonary CTL activity on day 5 was low for both groups (10% specific lysis). Secondary CTL activity at day 11 was higher for control mice than for IL-12-treated mice on day 11 (44 versus 34%), but not on day 13. Despite this overall enhancement of Th1-mediated immune functions, the IL-12 treatment increased severity of the disease. Following infection, control and IL-12-treated mice decreased their body weight to approximately 75% of their initial weight. After day 5, the control mice started to recover, while IL-12-treated mice did not begin recovering until day 9. Pulmonary viral titers were 1.6 +/- 0.3 TCID50 in controls at day 5 compared to 2.4 +/- 0.3 for IL-12-treated mice (P < 0.01). In addition, control mice had significantly less severe inflammation and damage on histologic examination. Serum TNFalpha concentrations, undetectable in control mice, were elevated by IL-12 treatment up to 80 pg/ml at day 5 and decreased to zero at day 13. It is concluded that IL-12 administration to influenza-infected mice induces a switch from a Th2- to a Th1-mediated response, but inhibits recovery probably through induction of TNFalpha.
白细胞介素12（IL-12）可引导未分化的辅助性T细胞（Th0）分化为1型辅助性T细胞（Th1），并诱导细胞介导的免疫反应。为评估IL-12对甲型流感病毒感染病程的影响，在第-1天至第+4天，每天给BALB/c小鼠腹腔注射1000 ng IL-12或生理盐水，共进行6次处理。该处理总体上增强了Th1介导的反应。在第5天，对照组小鼠肺中IFNγ浓度为1193±275 pg/100微升，IL-12处理组小鼠为3693±745 pg/100微升。在第13天，对照组小鼠中未检测到IFNγ水平，而IL-12处理组小鼠中为1335±220 pg/100微升。还在单细胞水平评估了纵隔淋巴结的细胞因子产生情况。IL-12处理增加了产生IL-2和IFNγ的细胞数量，减少了产生IL-4和IL-10的细胞数量。IL-12处理降低了抗流感抗体反应，尤其是抗流感IgG1抗体，导致IgG2a/IgG1比值增加。两组在第5天的原发性肺CTL活性均较低（特异性裂解率为10%）。在第11天，对照组小鼠的继发性CTL活性高于IL-12处理组小鼠（44%对34%），但在第13天并非如此。尽管Th1介导的免疫功能总体增强，但IL-12处理增加了疾病的严重程度。感染后，对照组和IL-12处理组小鼠的体重均降至初始体重的约75%。第5天后，对照组小鼠开始恢复，而IL-12处理组小鼠直到第9天才开始恢复。在第5天，对照组小鼠的肺病毒滴度为1.6±0.3 TCID50，而IL-12处理组小鼠为2.4±0.3（P<0.01）。此外，在组织学检查中，对照组小鼠的炎症和损伤明显较轻。对照组小鼠血清中未检测到的TNFα浓度，经IL-12处理后在第5天升高至80 pg/ml，在第13天降至零。结论是，给感染流感的小鼠注射IL-12可诱导从Th2介导的反应转变为Th1介导的反应，但可能通过诱导TNFα抑制恢复。
