title: Virus infection activates IL-1 beta and IL-18 production in human macrophages by a caspase-1-dependent pathway.
abstract: Monocytes and macrophages play a significant role in host's defense system, since they produce a number of cytokines in response to microbial infections. We have studied IL-1 beta, IL-18, IFN-alpha/beta, and TNF-alpha gene expression and protein production in human primary monocytes and GM-CSF-differentiated macrophages during influenza A and Sendai virus infections. Virus-infected monocytes released only small amounts of IL-1 beta or IL-18 protein, whereas 7- and 14-day-old GM-CSF-differentiated macrophages readily produced these cytokines. Constitutive expression of proIL-18 was seen in monocytes and macrophages, and the expression of it was enhanced during monocyte/macrophage differentiation. Expression of IL-18 mRNA was clearly induced only by Sendai virus, whereas both influenza A and Sendai viruses induced IL-1 beta mRNA expression. Since caspase-1 is known to cleave proIL-1 beta and proIL-18 into their mature, active forms, we analyzed the effect of a specific caspase-1 inhibitor on virus-induced IL-1 beta and IL-18 production. The release of IL-1 beta and IL-18, but not that of IFN-alpha/beta or TNF-alpha, was clearly blocked by the inhibitor. Our results suggest that the cellular differentiation is a crucial factor that affects the capacity of monocytes/macrophages to produce IL-1 beta and IL-18 in response to virus infections. Furthermore, the virus-induced activation of caspase-1 is required for the efficient production of biologically active IL-1 beta and IL-18.
authors.affiliation: Department of Virology, National Public Health Institute, Helsinki, Finland. jaana.pirhonen@ktl.fi
authors.forename: J
authors.initials: J
authors.lastname: Pirhonen
authors.forename: T
authors.initials: T
authors.lastname: Sareneva
authors.forename: M
authors.initials: M
authors.lastname: Kurimoto
authors.forename: I
authors.initials: I
authors.lastname: Julkunen
authors.forename: S
authors.initials: S
authors.lastname: Matikainen
mesh_terms: D020170:Caspase 1 / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002474:Cell-Free System / Q000502:physiology; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D009980:Influenza A virus / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D020382:Interleukin-18 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D007700:Kinetics; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D009000:Monocytes / Q000166:cytology / Q000201:enzymology / Q000378:metabolism / Q000821:virology; D011498:Protein Precursors / Q000096:biosynthesis; D015398:Signal Transduction / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D007375:Interleukin-1; D020382:Interleukin-18; D011498:Protein Precursors; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D020170:Caspase 1