First Author | Lee MH | Year | 2019 |
Journal | J Leukoc Biol | Volume | 106 |
Issue | 4 | Pages | 967-975 |
PubMed ID | 31216373 | Mgi Jnum | J:288648 |
Mgi Id | MGI:6364787 | Doi | 10.1002/JLB.3AB0518-180RR |
Citation | Lee MH, et al. (2019) The cytokine network type I IFN-IL-27-IL-10 is augmented in murine and human lupus. J Leukoc Biol 106(4):967-975 |
abstractText | 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. |