Human Cytokinome Analysis for Interferon Response.

Area of Science:

• Immunology
• Virology
• Molecular Biology

Background:

• Cytokines are crucial for immune responses, but only a few, like interferons (IFNs), mediate antiviral effects.
• Existing knowledge lacks a systematic understanding of how the broader cytokine repertoire interacts with and modulates IFN-driven antiviral responses.

Purpose of the Study:

• To conduct a large-scale screen of the human cytokinome (>240 members) to identify cytokines that modulate type I and type II IFN responses.
• To investigate the mechanisms by which identified cytokines enhance IFN signaling pathways (ISRE and GAS).
• To evaluate the potential of these cytokines to augment antiviral activity against various RNA viruses.

Main Methods:

• A comprehensive screen of over 240 human cytokines and chemokines.
• Utilized IFN-stimulated response element (ISRE) and IFN-γ activation sequence (GAS) reporter systems to assess cytokine activity.
• Employed Stat1 mutant fibroblasts to determine the role of Stat1 in cytokine-mediated IFN responses.
• Tested the antiviral efficacy of identified cytokines against encephalomyocarditis virus, vesicular stomatitis virus, and influenza virus.

Main Results:

• Identified several cytokine clusters that augment ISRE- and/or GAS-mediated IFN responses.
• Discovered novel IFN response modulators: betacellulin (BTC), interleukin 11 (IL-11), and IL-17F, which induce IFN responses in a time-dependent manner.
• Demonstrated that Stat1 is largely essential for the induction of endogenous IFN-β and IFN-stimulated genes by these cytokines.
• Confirmed that certain cytokines enhance the IFN-β response via the NF-κB pathway.
• Showed that novel IFN-like cytokines enhance the antiviral activity of IFN-α against multiple RNA viruses.

Conclusions:

• This study provides the most extensive analysis to date of cytokines enhancing IFN responses.
• Identified novel cytokines (BTC, IL-11, IL-17F) that augment Stat1 signaling, IFN-induced gene expression, and antiviral activities.
• These findings deepen the understanding of innate antiviral immunity and suggest potential therapeutic strategies by enhancing IFN-mediated antiviral actions.