Francisella tularensis Elicits IL-10 via a PGE(2)-Inducible Factor, to Drive Macrophage MARCH1 Expression and Class II Down-Regulation

Francisella tularensis is a bacterial pathogen that uses host-derived PGE(2) to subvert the host's adaptive immune responses in multiple ways. Francisella-induced PGE(2) acts directly on CD4 T cells to blunt production of IFN-γ. Francisella-induced PGE(2) can also elicit production of a >10 kDa soluble host factor termed FTMØSN (F. tularensis macrophage 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 PGE(2) 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 PGE(2) 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 PGE(2), these results suggest that a yet-to-be-identified PGE(2)-inducible host factor capable of inducing IL-10 is central to the immune evasion mechanisms of multiple important human pathogens.