IL-27: An endogenous constitutive repressor of human monocytes.

Abstract Interleukin (IL)-27 is a pleiotropic cytokine that initially was described as being pro-inflammatory and an inducer of T helper (Th)1 cells. In contrast, it has also been described as an anti-inflammatory cytokine in that it suppresses pro-inflammatory Th17 cells and induces anti-inflammatory IL-10 producing T regulatory (Tr)1 cells. While the majority of studies have been focused on the effects of IL-27 on T cells, human antigen-presenting cells express high levels of the IL-27 receptor ex vivo, in addition to being the major producer of IL-27. We report here that human monocytes are repressed by endogenous IL-27, in that the addition of an anti-IL-27 neutralizing antibody increases the production of pro-inflammatory cytokines ex vivo. We observed that neutralizing monocyte-derived IL-27 leads to increased IL-17A production by CD4+ T cells and a down-regulation of the IL-17 modulating ectonucleotidase CD39 on monocytes. The locus that contains the IL27 gene has been linked to susceptibility for type 1 diabetes (T1D). Interestingly, ex vivo monocytes from subjects with T1D produce more IL-27 suggesting this upregulation of IL-27 acts as a negative feedback loop to attempt to counterbalance the pro-inflammatory immune response in the disease state. In summary, we provide evidence that IL-27 is an endogenous regulator of human monocytes and has consequences on CD4+ T cell phenotype, particularly Th17 cells.