title: Francisella tularensis elicits IL-10 via a PGE₂-inducible factor, to drive macrophage MARCH1 expression and class II down-regulation.
abstract: 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 FTMØSN (F. tularensismacrophage supernatant), which acts on IFN-γ pre-activated MØ to down-regulate MHC class II expression via a ubiquitin-dependent mechanism, blocking antigen presentation to CD4 T cells. Here, we report that FTMØSN-induced down-regulation of MØ class II is the result of the induction of MARCH1, and that MØ expressing MARCH1 "resistant" class II molecules are resistant to FTMØSN-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 FTMØSN. However, use of IL-10 knockout MØ established that IL-10 is not the active factor in FTMØSN, but rather that Francisella-elicited PGE₂ drives production of a >10 kDa host factor distinct from IL-10. This factor then drives MØ 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.
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, United States of America.
authors.forename: Danielle
authors.initials: D
authors.lastname: Hunt
authors.forename: Justin E
authors.initials: JE
authors.lastname: Wilson
authors.forename: Karis A
authors.initials: KA
authors.lastname: Weih
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ishido
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Harton
authors.forename: Paul A
authors.initials: PA
authors.lastname: Roche
authors.forename: James R
authors.initials: JR
authors.lastname: Drake
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D015232:Dinoprostone / Q000502:physiology; D015536:Down-Regulation; D005604:Francisella tularensis / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis*; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis* / Q000502:physiology; D015854:Up-Regulation
chemical_list: D000949:Histocompatibility Antigens Class II; D016753:Interleukin-10; C528121:MARCHF1 protein, human; D044767:Ubiquitin-Protein Ligases; D015232:Dinoprostone