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

Cell Rep. 2022 Jun 28;39(13):110989. doi: 10.1016/j.celrep.2022.110989.


The interleukin-12 (IL-12) family comprises the only heterodimeric cytokines mediating diverse functional effects. We previously reported a striking bimodal IL-12p70 response to lipopolysaccharide (LPS) stimulation in healthy donors. Herein, we demonstrate that interferon β (IFNβ) is a major upstream determinant of IL-12p70 production, which is also associated with numbers and activation of circulating monocytes. Integrative modeling of proteomic, genetic, epigenomic, and cellular data confirms IFNβ as key for LPS-induced IL-12p70 and allowed us to compare the relative effects of each of these parameters on variable cytokine responses. Clinical relevance of our findings is supported by reduced IFNβ-IL-12p70 responses in patients hospitalized with acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or chronically infected with hepatitis C (HCV). Importantly, these responses are resolved after viral clearance. Our systems immunology approach defines a better understanding of IL-12p70 and IFNβ in healthy and infected persons, providing insights into how common genetic and epigenetic variation may impact immune responses to bacterial infection.

Keywords: CP: Immunology; Cytokine variability; IL-12p70; TLR4 immune responses; systems immunology; type I interferons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • COVID-19 / immunology
  • COVID-19 / metabolism
  • COVID-19 / virology
  • Cytokines / immunology
  • Cytokines / metabolism
  • Humans
  • Interferon-beta* / immunology
  • Interferon-beta* / metabolism
  • Interleukin-12* / immunology
  • Interleukin-12* / metabolism
  • Lipopolysaccharides / pharmacology
  • Proteomics
  • SARS-CoV-2 / immunology
  • Toll-Like Receptor 4*


  • Cytokines
  • Lipopolysaccharides
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Interleukin-12
  • Interferon-beta