Salmonella infection does not increase expression and activity of the high affinity IL-12 receptor.
Expression of high affinity IL-12 receptors is required for IL-12-mediated IFN-gamma production. Activation of this pathway has been shown to be critical in generating optimal cell-mediated immunity. Therefore, increased IL-12 receptor expression might be expected in the host response after infection by an intracellular bacterial pathogen. In the present study, we have made the surprising discovery that infection with Salmonella results in an early reduction of high affinity IL-12 receptor expression and activation. After oral inoculation with Salmonella, the level of mRNA expression encoding IL-12 receptor beta2 (IL-12Rbeta2) subunit was diminished 12 h postinfection in the mesenteric lymph nodes and subsequently in the spleen. Furthermore, decreased IL-12Rbeta2 mRNA expression was observed in CD4+ T lymphocytes isolated from the mesenteric lymph nodes and spleens of infected mice. Attenuated IL-12Rbeta2 mRNA expression correlated with reduced receptor signaling, as demonstrated by reduced IL-12-induced STAT4 phosphorylation in enriched T lymphocytes isolated from the mesenteric lymph nodes and spleens of Salmonella-infected mice. These in vivo results were substantiated with an in vitro model system. In this model system, T lymphocytes cocultured with Salmonella-infected macrophages expressed less IL-12Rbeta2 mRNA. The cocultured T cells were also less responsive to IL-12 as assessed by reduced phosphorylation of STAT4 and limited IFN-gamma secretion. Together, these studies suggest that Salmonella can limit an optimal host immune response by reducing the expression and activity of high affinity IL-12 receptors.
Elhofy
A
A
Department of Biology, University of North Carolina, Charlotte, NC 28223, USA.
Marriott
I
I
Bost
K L
KL
D000818:Animals; D016516:CD4-CD8 Ratio; D002478:Cells, Cultured; D018920:Coculture Techniques; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007441:Intubation, Gastrointestinal; D008198:Lymph Nodes / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D008643:Mesentery; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D053707:Receptors, Interleukin-12; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012260:Ribonucleases / Q000378:metabolism; D050797:STAT4 Transcription Factor; D012475:Salmonella / Q000276:immunology; D012481:Salmonella Infections, Animal / Q000276:immunology* / Q000378:metabolism*; D013154:Spleen / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism
D004268:DNA-Binding Proteins; C508443:Il12rb2 protein, mouse; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D011994:Recombinant Proteins; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D015534:Trans-Activators; D018664:Interleukin-12; D007371:Interferon-gamma; D012260:Ribonucleases