Early IFNβ secretion determines variable downstream IL-12p70 responses upon TLR4 activation.

Area of Science:

• Immunology
• Systems Immunology
• Cytokine Biology

Background:

• The interleukin-12 (IL-12) family of cytokines plays a crucial role in immune responses.
• Previous work identified a unique bimodal IL-12p70 response to lipopolysaccharide (LPS) in healthy individuals.

Purpose of the Study:

• To identify upstream regulators of IL-12p70 production.
• To investigate the role of interferon beta (IFNβ) in LPS-induced IL-12p70.
• To explore the clinical relevance of IFNβ-IL-12p70 responses in viral infections.

Main Methods:

• Integrative modeling of proteomic, genetic, epigenomic, and cellular data.
• Analysis of cytokine responses in healthy donors and patients with SARS-CoV-2 and HCV infections.
• Assessment of monocyte numbers and activation.

Main Results:

• Interferon beta (IFNβ) was confirmed as a key upstream determinant of IL-12p70 production following LPS stimulation.
• IFNβ-IL-12p70 responses were associated with monocyte characteristics.
• Reduced IFNβ-IL-12p70 responses were observed in patients with acute SARS-CoV-2 and chronic HCV infections.
• These responses normalized after viral clearance.

Conclusions:

• IFNβ is a critical regulator of LPS-induced IL-12p70 production.
• Impaired IFNβ-IL-12p70 responses are linked to severe SARS-CoV-2 and chronic HCV infections.
• Viral clearance restores normal IFNβ-IL-12p70 immune responses.
• This study provides insights into genetic and epigenetic influences on immune responses to bacterial infection.