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Leishmania major activates IL-1 alpha expression in macrophages through a MyD88-dependent pathway.
Title | Leishmania major activates IL-1 alpha expression in macrophages through a MyD88-dependent pathway. |
Publication Type | Journal Article |
Year of Publication | 2002 |
Authors | Hawn, TR, Ozinsky, A, Underhill, DM, Buckner, FS, Akira, S, Aderem, A |
Journal | Microbes Infect |
Volume | 4 |
Issue | 8 |
Pagination | 763-71 |
Date Published | 2002 Jul |
ISSN | 1286-4579 |
Keywords | Adaptor Proteins, Signal Transducing, Animals, Antigens, Differentiation, Cell Line, Enzyme-Linked Immunosorbent Assay, Gene Expression Regulation, Genes, Reporter, Interleukin-1, Leishmania major, Lipopolysaccharides, Macrophage Activation, Macrophages, Mice, Myeloid Differentiation Factor 88, Polymerase Chain Reaction, Promoter Regions, Genetic, Receptors, Immunologic, RNA, Messenger, Signal Transduction, Transfection |
Abstract | 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. |
Alternate Journal | Microbes Infect. |
PubMed ID | 12270723 |