Virus infection activates IL-1 beta and IL-18 production in human macrophages by a caspase-1-dependent pathway

Monocytes and macrophages play a significant role in host's defense system, since they produce a number of cytokines in response to microbial infectio ns. We have studied IL-1 beta, IL-18, IFN-alpha/beta, and TNF-alpha gene ex pression and protein production in human primary monocytes and GM-CSF-diffe rentiated macrophages during influenza A and Sendai virus infections, Virus -infected monocytes released only small amounts of IL-1 beta or IL-18 prote in, whereas: 7- and 14-day-old GM-CSF-differentiated macrophages readily pr oduced these cytokines. Constitutive expression of proIL-18 was seen in mon ocytes and macrophages, and the expression of it was enhanced during monocy te/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 productio n, The release of IL-1 beta and IL-18, but not that of IFN-alpha/beta or TN F-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 i nfections; Furthermore, the virus-induced activation of caspase-1 is requir ed for the efficient production of biologically active IL-1 beta and IL-18.