Induction of IFN-alphabeta enables Listeria monocytogenes to suppress macrophage activation by IFN-gamma.
Production of type I interferon (IFN; IFN-alphabeta) increases host susceptibility to Listeria monocytogenes, whereas type II IFN (IFN-gamma) activates macrophages to resist infection. We show that these opposing immunological effects of IFN-alphabeta and IFN-gamma occur because of cross talk between the respective signaling pathways. We found that cultured macrophages infected with L. monocytogenes were refractory to IFN-gamma treatment as a result of down-regulation of the IFN-gamma receptor (IFNGR). The soluble factor responsible for these effects was identified as host IFN-alphabeta. Accordingly, macrophages and dendritic cells (DCs) showed reduced IFNGR1 expression and reduced responsiveness to IFN-gamma during systemic infection of IFN-alphabeta-responsive mice. Furthermore, the increased resistance of mice lacking the IFN-alphabeta receptor (IFNAR(-/-)) to L. monocytogenes correlated with increased expression of IFN-gamma-dependent activation markers by macrophages and DCs and was reversed by depletion of IFN-gamma. Thus, IFN-alphabeta produced in response to bacterial infection and other stimuli antagonizes the host response to IFN-gamma by down-regulating the IFNGR. Such cross talk permits prioritization of IFN-alphabeta-type immune responses and may contribute to the beneficial effects of IFN-beta in treatment of inflammatory diseases such as multiple sclerosis.
Rayamajhi
Manira
M
National Jewish Health, Denver, CO 80206, USA.
Humann
Jessica
J
Penheiter
Kristi
K
Andreasen
Karl
K
Lenz
Laurel L
LL
D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D015536:Down-Regulation; D005260:Female; D007113:Immunity, Innate; D007370:Interferon Type I / Q000276:immunology / Q000378:metabolism*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D008089:Listeria monocytogenes; D008088:Listeriosis / Q000276:immunology*; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D017471:Receptors, Interferon / Q000037:antagonists & inhibitors / Q000378:metabolism; D000096743:Interferon gamma Receptor
D007370:Interferon Type I; D007371:Interferon-gamma; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor