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Leishmania major
is an etiological agent of cutaneous leishmaniasis. The parasite primarily infects immune sentinel cells, specifically macrophages and dendritic cells, in the mammalian host. Infection is receptor mediated and is known to involve parasite binding to cell surface protein complement receptor 3 (CR3, Mac-1, CD11b/CD18). Engagement of CR3 by various ligands inhibits production of interleukin-12 (IL-12), the cytokine that drives anti-leishmanial T helper 1-type immune responses. Likewise,
L. major
infection inhibits IL-12 production and activation of host macrophages. Our data indicate that in the absence of CR3,
L. major
-infected bone marrow-derived macrophages produce more IL-12 and nitric oxide compared to WT cells upon LPS stimulation. We therefore investigated multiple signaling pathways by which
L. major
may inhibit IL-12 transcription through CR3 ligation. We demonstrate that
L. major
infection does not elicit significant NFκB p65, MAPK, IRF-1, or IRF-8 activation in WT or CD11b deficient macrophages. Furthermore, infection neither inhibits LPS-induced MAPK or NFκB activation, nor blocks IFN-γ-activated IRF-1 and IRF-8. ETS-mediated transcription, however, is inhibited by
L. major
infection independently of CR3. Our data indicate that
L. major
mediated inhibition of IL-12 occurs through CR3 engagement, however the mechanism of inhibition is independent of NFκB, MAPK, IRF, and ETS.