Mencacci A, Cenci E, Del Sero G, Fé d'Ostiani C, Mosci P, Trinchieri G, Adorini L, Romani L
Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Italy.
J Immunol. 1998 Dec 1;161(11):6228-37.
IL-12 is both required and prognostic for Th1 development in mice with Candida albicans infection. To delineate further the physiologic role of IL-12 in antifungal immunity, mice deficient for this cytokine were assessed for susceptibility to C. albicans infections, and for parameters of innate and adaptive immunity. IL-12-deficient mice were highly susceptible to gastrointestinal infection or to reinfection and showed elevated production of Candida-specific IgE and IL-4 and defective production of IFN-gamma. The failure to mount protective Th1 responses occurred despite the presence of an unimpaired innate antifungal immune response, which correlated with unaltered IFN-gamma production, but defective production of, and responsiveness to, inhibitory IL-10. IL-10 or IL-12 neutralization increased the innate antifungal resistance in wild-type mice. However, in IL-12-deficient mice, treatment with exogenous IL-12 or IL-10 impaired IL-4 production and increased resistance to infection, through a negative effect on the CTLA-4/B7-2 costimulatory pathway. These results confirm the obligatory role of IL-12 in the induction of anticandidal Th1 responses, and indicate the existence of a positive regulatory loop between IL-12 and IL-10 that may adversely affect the innate antifungal response, but is required for optimal costimulation of IL-12-dependent CD4+ Th1 cells.
白细胞介素-12对于白色念珠菌感染小鼠的Th1细胞发育既是必需的，也是预后的指标。为了进一步阐明白细胞介素-12在抗真菌免疫中的生理作用，对缺乏这种细胞因子的小鼠进行了白色念珠菌感染易感性评估，以及先天性和适应性免疫参数评估。白细胞介素-12缺陷小鼠对胃肠道感染或再感染高度易感，且念珠菌特异性IgE和白细胞介素-4产生增加，而干扰素-γ产生存在缺陷。尽管存在未受损的先天性抗真菌免疫反应，但仍未能产生保护性Th1反应，这与干扰素-γ产生未改变相关，但抑制性白细胞介素-10的产生和反应性存在缺陷。在野生型小鼠中，中和白细胞介素-10或白细胞介素-12可增加先天性抗真菌抵抗力。然而，在白细胞介素-12缺陷小鼠中，通过对外周血淋巴细胞抗原4/ B7-2共刺激途径的负面影响，用外源性白细胞介素-12或白细胞介素-10治疗可损害白细胞介素-4的产生并增加对感染的抵抗力。这些结果证实了白细胞介素-12在诱导抗念珠菌Th1反应中的必要作用，并表明白细胞介素-12和白细胞介素-10之间存在一个正调节环，该调节环可能对先天性抗真菌反应产生不利影响，但对于白细胞介素-12依赖性CD4+ Th1细胞的最佳共刺激是必需的。
