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Microbes Infect. 2002 Jul;4(8):763-71.

Leishmania major activates IL-1 alpha expression in macrophages through a MyD88-dependent pathway.

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Division of Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA 98195, USA.


Leishmania species present unusual challenges to the immune system with their capacity to downregulate inflammatory responses as well as their ability to live within macrophages. Although toll-like receptor (TLR) pathways have been implicated in the recognition of several classes of pro-inflammatory microbes, it is not known if pathogens with anti-inflammatory properties activate the host response through this family of proteins. In this study, Leishmania major stimulation of cytokine promoter-luciferase reporter constructs was examined in transfected macrophages to detect early signs of cellular activation. L. major selectively activated the promoter region of IL-1 alpha, but not IL-6, IL-8, IL-10, or an NF-kappa B reporter. IL-1 alpha mRNA expression was also stimulated by L. major, although at lower levels than lipopolysacharide-stimulated macrophages. No IL-1 alpha protein was detectable in stimulated cell lysates or culture supernatants. Transfection of macrophages with a dominant-negative version of myeloid differentiation factor 88 (MyD88), an adaptor protein which interacts with TLRs, inhibited activation of the IL-1 alpha promoter. Furthermore, stimulation of IL-1 alpha RNA expression by L. major was inhibited in peritoneal macrophages from MyD88-/- as compared to MyD88+/+ mice. These observations indicate that L. major stimulates IL-1 alpha promoter activity and mRNA expression in macrophages through MyD88-dependent pathways. However, additional anti-inflammatory pathways must also be activated which downregulate transcription and ultimately inhibit translation of the IL-1 alpha protein. Examination of promoter activation is a powerful tool for understanding the early events in macrophage activation for anti-inflammatory pathogens such as Leishmania that have mechanisms to downregulate transcription and translation.

[Indexed for MEDLINE]

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