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Virus infection activates IL-1 beta and IL-18 production in human macrophages by a caspase-1-dependent pathway
J Pirhonen1, T Sareneva, M Kurimoto
1Department of Virology, National Public Health Institute, Helsinki, Finland. jaana.pirhonen@ktl.fi
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.
Insights
Monocyte and macrophage differentiation enhances their ability to produce IL-1 beta and IL-18 cytokines during viral infections. Caspase-1 activation is essential for releasing these key inflammatory mediators.
Area of Science:
- Immunology
- Cell Biology
- Virology
Background:
- Monocytes and macrophages are crucial immune cells involved in host defense against microbial infections.
- These cells produce various cytokines, including IL-1 beta, IL-18, IFN-alpha/beta, and TNF-alpha, which mediate inflammatory responses.
- Understanding cytokine production during viral infections is vital for developing effective therapeutic strategies.
Purpose of the Study:
- To investigate the gene expression and protein production of key cytokines (IL-1 beta, IL-18, IFN-alpha/beta, TNF-alpha) in human monocytes and macrophages upon influenza A and Sendai virus infection.
- To determine the role of cellular differentiation in modulating cytokine responses.
- To elucidate the involvement of caspase-1 in the processing and release of virus-induced cytokines.
Main Methods:
- Primary human monocytes and GM-CSF-differentiated macrophages were infected with influenza A and Sendai viruses.
- Gene expression (mRNA) and protein production of IL-1 beta, IL-18, IFN-alpha/beta, and TNF-alpha were analyzed.
- The effect of a specific caspase-1 inhibitor on cytokine release was assessed.
Main Results:
- Virus-infected monocytes produced limited IL-1 beta and IL-18 protein, while differentiated macrophages showed robust production.
- Both influenza A and Sendai viruses induced IL-1 beta mRNA, while only Sendai virus induced IL-18 mRNA.
- Caspase-1 inhibition significantly blocked the release of IL-1 beta and IL-18, but not IFN-alpha/beta or TNF-alpha.
Conclusions:
- Cellular differentiation is a critical factor influencing the capacity of monocytes/macrophages to produce IL-1 beta and IL-18 in response to viral stimuli.
- Virus-induced activation of caspase-1 is essential for the efficient production of biologically active IL-1 beta and IL-18.
- These findings highlight the distinct roles of monocytes and differentiated macrophages in antiviral immunity and cytokine regulation.