The cytokine network type I IFN-IL-27-IL-10 is augmented in murine and human lupus

J Leukoc Biol. 2019 Oct;106(4):967-975. doi: 10.1002/JLB.3AB0518-180RR. Epub 2019 Jun 19.


IL-10 is elevated in the autoimmune disease systemic lupus erythematosus (SLE). Here, we show that conventional dendritic cells (cDCs) from predisease lupus-prone B6.NZM Sle1/Sle2/Sle3 triple congenic (TCSle) mice produce more IL-10 than wild-type congenic cDCs upon TLR stimulation, and this overproduction is prevented by blocking the type I IFN receptor (IFNAR) with specific Abs. Priming wild-type cDCs with type I IFN mimics the IL-10 overproduction of TCSle cDCs. The MAPK ERK is more phosphorylated in lupus cDCs, partially contributing to IL-10 overproduction. Moreover, we found that TCSle cDCs express higher levels of IL-27 upon TLR7/TLR9 stimulation, and IFNAR blockade reduced IL-27 levels in TCSle cDCs. These results suggest that dysregulated type I IFNs in cDCs contribute to the increased IL-10 and IL-27 in SLE. Since IL-27 neutralization did not inhibit TLR-induced IL-10 production, we propose that type I IFNs enhanced IL-10 in TCSle cDCs independently from IL-27. Moreover, RNA sequencing analysis of a cohort of SLE patients reveals higher gene expression of these cytokines in SLE patients expressing a high IFN signature. Since IL-27 and IL-10 have both pro- and anti-inflammatory effects, our results also suggest that these cytokines can be modulated by the therapeutic IFN blockade in trials in SLE patients and have complex effects on the autoimmune response.

Keywords: MAPK; cytokines; innate immunity; lupus; type I interferons.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD40 Antigens / metabolism
  • Chemokine CXCL10 / metabolism
  • Dendritic Cells / drug effects
  • Dendritic Cells / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Humans
  • Imidazoles / pharmacology
  • Interferon Type I / metabolism*
  • Interleukin-10 / metabolism*
  • Interleukin-27 / metabolism*
  • Ligands
  • Lipopolysaccharides / pharmacology
  • Lupus Erythematosus, Systemic / immunology*
  • Lupus Erythematosus, Systemic / pathology
  • Mice, Inbred C57BL
  • Oligodeoxyribonucleotides / pharmacology
  • Receptor, Interferon alpha-beta / metabolism
  • Toll-Like Receptors / metabolism


  • CD40 Antigens
  • CPG-oligonucleotide
  • Chemokine CXCL10
  • Imidazoles
  • Interferon Type I
  • Interleukin-27
  • Ligands
  • Lipopolysaccharides
  • Oligodeoxyribonucleotides
  • Toll-Like Receptors
  • Interleukin-10
  • Receptor, Interferon alpha-beta
  • Extracellular Signal-Regulated MAP Kinases
  • resiquimod