Kostka Susanna Lopez, Knop Jürgen, Konur Abdo, Udey Mark C, von Stebut Esther
Department of Dermatology, Johannes Gutenberg-University Mainz, Mainz, Germany.
J Invest Dermatol. 2006 Jul;126(7):1582-9. doi: 10.1038/sj.jid.5700309. Epub 2006 Apr 27.
IL-1alpha/beta released by infected dendritic cells (DC) plays a critical role in the development of protective immunity against Leishmania major. Previous studies demonstrated that treatment of susceptible BALB/c mice with IL-1alpha during T-cell priming (days 1-3 post-infection) induced T helper (Th)1-mediated protection. In contrast, we now demonstrate that prolonged treatment with IL-1alpha (for 3 weeks) worsened disease outcome. To characterize the receptor involved, L. major infections in IL-1 receptor type I (IL-1RI) knockout mice were studied. In C57BL/6 IL-1RI-/- mice, the IL-1alpha-mediated protective effect was abrogated. The course of high-dose infection (2 x 10(5) parasites) in IL-1RI-/- mice was not different from controls. Surprisingly, in low-dose infections (10(3) parasites), IL-1RI-/- mice developed approximately 50% smaller lesions compared to wild types, decreased parasite loads and increased IFNgamma/IL-4 ratios. Interestingly, naive Th0 and Th2, but not Th1, cells expressed IL-1RI ex vivo. We conclude that IL-1RI mediates the effect of IL-1alpha in leishmaniasis in C57BL/6 mice. In addition, IL-1 appears to play distinct roles in Th education and maintenance. In early phases of physiologically relevant, low-dose L. major infections, IL-1 facilitates Th1 development from Th0 cells, whereas later on IL-1RI signaling promotes Th2 expansion and worsens disease outcome. Effects of IL-1 on disease outcome may be related to levels of IL-1RI on Th subpopulations.
被感染的树突状细胞（DC）释放的白细胞介素-1α/β（IL-1α/β）在针对硕大利什曼原虫的保护性免疫发展中起关键作用。先前的研究表明，在T细胞致敏期间（感染后第1 - 3天）用IL-1α治疗易感的BALB/c小鼠可诱导辅助性T细胞（Th）1介导的保护作用。相比之下，我们现在证明用IL-1α进行长期治疗（持续3周）会使疾病结局恶化。为了确定所涉及的受体，对白细胞介素-1受体I型（IL-1RI）基因敲除小鼠中的硕大利什曼原虫感染进行了研究。在C57BL/6 IL-1RI - / - 小鼠中，IL-1α介导的保护作用被消除。IL-1RI - / - 小鼠中高剂量感染（2×10⁵个寄生虫）的病程与对照组无异。令人惊讶的是，在低剂量感染（10³个寄生虫）中，与野生型相比，IL-1RI - / - 小鼠的病变大小约小50%，寄生虫负荷降低，且干扰素γ/白细胞介素-4比值升高。有趣的是，未经致敏的Th0和Th2细胞（而非Th1细胞）在体外表达IL-1RI。我们得出结论，IL-1RI介导了IL-1α在C57BL/6小鼠利什曼病中的作用。此外，IL-1似乎在Th细胞的分化和维持中发挥不同作用。在生理相关的低剂量硕大利什曼原虫感染的早期阶段，IL-1促进Th0细胞向Th1细胞分化，而在后期，IL-1RI信号传导促进Th2细胞扩增并使疾病结局恶化。IL-1对疾病结局的影响可能与Th亚群上IL-1RI的水平有关。
