Regulation of virus-induced IL-12 and IL-23 expression in human macrophages.
IL-23 is a novel cytokine that promotes the proliferation of naive and memory T cells and stimulates their IFN-gamma production. Besides functional similarities, IL-23 bears structural resemblance to IL-12. Biologically active IL-23 is a heterodimer whose p40 subunit is identical to IL-12p40 while its p19 subunit is distantly related to IL-12p35. In the present study we demonstrate that human monocyte-derived macrophages are able to produce IL-23 in response to virus infection. Sendai virus stimulates the expression of p19 and p40 mRNAs in macrophages. Furthermore, it enhances p35 mRNA expression and the production of IL-12. Influenza A virus, in contrast, fails to stimulate IL-12 or IL-23 expression in macrophages. IL-12 and IL-23 contribute to the IFN-gamma-inducing activity that cell culture supernatant from Sendai virus-infected macrophages show in NK-92 cells. The induction of IFN-gamma production occurs in concert with IFN-alphabeta and IL-18, which are also secreted from the virus-infected cells. The IFN-gamma-inducing activity is inhibited by IL-4, which down-regulates the transcription of p19 and p40 genes and the secretion of IFN-alphabeta, IL-12, and IL-18. IFN-gamma, in contrast, up-regulates the p19 and p40 mRNA expression in Sendai virus infection. Thus, IL-4 and IFN-gamma serve as opposing factors in the regulation of IFN-gamma-inducing cytokines, including IL-23, in macrophages.
Pirhonen
Jaana
J
Department of Microbiology, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland. jaana.pirhonen@ktl.fi
Matikainen
Sampsa
S
Julkunen
Ilkka
I
D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D015967:Gene Expression Regulation, Viral / Q000276:immunology*; D006801:Humans; D009980:Influenza A virus / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000502:physiology; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000235:genetics; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D015847:Interleukin-4 / Q000494:pharmacology; D007378:Interleukins / Q000096:biosynthesis* / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D021122:Protein Subunits / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D029082:Sendai virus / Q000276:immunology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D016207:Cytokines; C508858:IL12A protein, human; C508840:IL23A protein, human; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D021122:Protein Subunits; D012333:RNA, Messenger; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma