Francisella tularensis Elicits IL-10 via a PGE2-Inducible Factor, to Drive Macrophage MARCH1 Expression and Class II Down-Regulation
| Autor: | Paul A. Roche, Satoshi Ishido, James R. Drake, Jonathan A. Harton, Justin E. Wilson, Danielle Hunt, Karis A. Weih |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
CD4-Positive T-Lymphocytes
Immune Cells Ubiquitin-Protein Ligases Antigen presentation Immunology Antigen-Presenting Cells Down-Regulation Antigen Processing and Recognition Biology Major histocompatibility complex Biochemistry Dinoprostone Microbiology Major Histocompatibility Complex 03 medical and health sciences 0302 clinical medicine Immune system Molecular Cell Biology Macrophage Humans Francisella tularensis 030304 developmental biology Host factor 0303 health sciences MHC class II Multidisciplinary Macrophages Histocompatibility Antigens Class II Proteins Major Histocompatibility Antigens biology.organism_classification Interleukin-10 Up-Regulation Interleukin 10 biology.protein Membranes and Sorting 030215 immunology Research Article |
| Zdroj: | PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | Francisella tularensis is a bacterial pathogen that uses host-derived PGE2 to subvert the host's adaptive immune responses in multiple ways. Francisella-induced PGE2 acts directly on CD4 T cells to blunt production of IFN-γ. Francisella-induced PGE2 can also elicit production of a >10 kDa soluble host factor termed FTMOSN (F. tularensis macrophage supernatant), which acts on IFN-γ pre-activated MO to down-regulate MHC class II expression via a ubiquitin-dependent mechanism, blocking antigen presentation to CD4 T cells. Here, we report that FTMOSN-induced down-regulation of MO class II is the result of the induction of MARCH1, and that MO expressing MARCH1 “resistant” class II molecules are resistant to FTMOSN-induced class II down-regulation. Since PGE2 can induce IL-10 production and IL-10 is the only reported cytokine able to induce MARCH1 expression in monocytes and dendritic cells, these findings suggested that IL-10 is the active factor in FTMOSN. However, use of IL-10 knockout MO established that IL-10 is not the active factor in FTMOSN, but rather that Francisella-elicited PGE2 drives production of a >10 kDa host factor distinct from IL-10. This factor then drives MO IL-10 production to induce MARCH1 expression and the resultant class II down-regulation. Since many human pathogens such as Salmonella typhi, Mycobacterium tuberculosis and Legionella pneumophila also induce production of host PGE2, these results suggest that a yet-to-be-identified PGE2-inducible host factor capable of inducing IL-10 is central to the immune evasion mechanisms of multiple important human pathogens. |
| Databáze: | OpenAIRE |
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