The salient feature of dendritic cells (DC) is the initiation of appropriate adaptive immune responses by discriminating between pathogens. Using a prototypic model of intracellular infection, we previously showed that Leishmania major parasites prime human DC for efficient interleukin-12 (IL-12) secretion. L. major infection is associated with self-limiting cutaneous disease and powerful immunity. In stark contrast, the causative agent of visceral leishmaniasis, Leishmania donovani, does not prime human DC for IL-12 production. Here, we report that DC priming by L. major infection results in the early activation of NF-B transcription factors and the up-regulation and nuclear translocation of interferon regulatory factor 1 (IRF-1) and IRF-8. The inhibition of NF-B activation by the pretreatment of DC with caffeic acid phenethyl ester blocks L. major-induced IRF-1 and IRF-8 activation and IL-12 expression. We further demonstrate that IRF-1 and IRF-8 obtained from L. major-infected human DC specifically bind to their consensus binding sites on the IL-12p35 promoter, indicating that L. major infection either directly stimulates a signaling cascade or induces an autocrine pathway that activates IRF-1 and IRF-8, ultimately resulting in IL-12 transcription.Leishmania major is the causative agent of cutaneous leishmaniasis, which is characterized by the development of lesions at sand fly bite sites. These cutaneous lesions ulcerate, resolve, and ultimately stimulate powerful immunity against the disease. Robust induction of this immunity is the basis of leishmanization, an effective vaccination procedure in which the inoculation of live L. major has been used with great success (12); safety concerns, however, have led to the abandonment of such vaccination (17). In contrast to L. major, Leishmania donovani causes visceral leishmaniasis, a severe systemic illness that is often fatal if untreated.Healing of cutaneous leishmaniasis has been attributed to the development of a strong Th1 immune response in the vertebrate host. Interleukin-12 (IL-12) is up-regulated in L. major-infected human dendritic cells (DC), whereas visceral leishmaniasis agents do not induce IL-12 production (28). Those previous studies revealed that L. donovani does not actively inhibit IL-12 production; rather, L. major primes human DC for IL-12 production. This strong induction of IL-12 by L. major-infected DC sets the stage for a strong and robust Th1 immune response that leads to lesion healing and immunity against the disease. Elucidation of the mechanisms that mediate the strong immunity elicited by L. major will undoubtedly have consequences for vaccine development against all Leishmania species as well as other infections, where strong cell-mediated immune responses are essential for resistance.IL-12 belongs to a family of cytokines including IL-23, IL-27, and ciliary neutrotrophic factor receptor (CNTFR). The bioactive form of this proinflammatory cytokine is a unique heterodimeric protein composed of p35 and p40 subunits that are encoded by...
Leishmania major infected human dendritic cells (DCs) exhibit a marked induction of IL-12, ultimately promoting a robust Th1-mediated response associated with parasite killing and protective immunity. The host cell transcription machinery associated with the specific IL-12 induction observed during L. major infection remains to be thoroughly elucidated. In this study, we utilized Affymetrix Genechips to globally assess the host cell genes and pathways associated with early L. major infection in human myeloid-derived DCs. Our data revealed 728 genes were significantly differentially expressed and molecular signaling pathway revealed that the type I IFN pathway was significantly enriched. Addition of a neutralizing type I IFN decoy receptor blocked the expression of IRF7 and IL-12p40 during DC infection, indicating the L. major induced expression of IL-12p40 is dependent upon the type I IFN signaling pathway. In stark contrast, IL-12p40 expression is not elicited by Leishmania donovani, the etiological agent of deadly visceral leishmaniasis. Therefore, we examined the gene expression profile for several IFN response genes in L. major versus L. donovani DC infections. Our data revealed that L. major, but not L. donovani, induces expression of IRF2, IRF7, and IFIT5, implicating the regulation of type I IFN associated signaling pathways as mediating factors toward the production of IL-12.
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