Elevated interleukin‐27 levels in human neonatal macrophages regulate indoleamine dioxygenase in a STAT‐1 and STAT‐3‐dependent manner

Abstract

SummaryMicrobial infections are a major cause of infant mortality as a result of limitations in immune defences. ) is a heterodimeric cytokine produced primarily by leucocytes and is immunosuppressive toward lymphocytes and leucocytes. Our laboratory demonstrated that human neonatal macrophages express IL-27 more abundantly than adult macrophages. Similarly in mice, IL-27 expression is elevated early in life and maintained through infancy. To determine IL-27-regulated mechanisms that may limit immunity, we evaluated the expression of a number of genes in response to this cytokine in primary human neonatal macrophages. Indoleamine 2,3-dioxygenase (IDO) gene expression was increased dose-responsively by IL-27. We have previously demonstrated inhibition of T-cell proliferation and cytokine production by neonatal macrophagegenerated IL-27, and IDO is often implicated in this negative regulation. An increase in IDO protein was demonstrated by immunofluorescence microscopy and was consistent with increased enzyme activity following treatment with IL-27. Inclusion of a soluble receptor to neutralize endogenous IL-27, decreased IDO expression and activity compared with untreated macrophages. In response to IL-27, neonatal macrophages phosphorylate signal transdcuer and activator of transcription 1 (STAT-1) and STAT-3. Both transcription factors are recruited to the IDO regulatory region. STAT-3 dominates during steady-state regulation by lower levels of endogenous IL-27 production. A shift to enhanced STAT-1 recruitment occurs during increased levels of exogenously supplied IL-27. These data suggest an interesting interplay of STAT-1 and STAT-3 to regulate IDO activity and immunosuppression in response to different levels of IL-27 in the microenvironment of the immune response that may further our understanding of this interesting cytokine.

Cigarette Smoke Induction of Interleukin-27/WSX-1 Regulates the Differentiation of Th1 and Th17 Cells in a Smoking Mouse Model of Emphysema

“…In the current study, both p-STAT1 and p-STAT3 were increased by the addition of IL-27 into cells under Th1 condition, which in line with the expression of T-bet and IFN-γ, suggesting the activation of STAT1 and STAT3 are all mediating T-bet induction in the course of IL-27 initiated Th1 commitment. This result is in agreement with a study by Jung et al, which found that elevated IL-27 levels in primary human neonatal macrophages regulated indoleamine dioxygenase in a STAT-1 and STAT-3-dependent manner (41). Activation of STAT3 by IL-6 and IL-23 drives the production of IL-17 by CD4 + T cells.…”

Murine myeloid‐derived suppressor cells are a source of elevated levels of interleukin‐27 in early life and compromise control of bacterial infection

“…In this report, we add to the current body of knowledge regarding IL‐27 levels in early life. IL‐27 gene expression and protein levels are increased in human neonatal macrophages and the spleens of mice through the first 3 weeks of life . In a previous report, macrophages producing IL‐27 were more abundant in mouse spleens .…”

“…With these observations in mind, we explored the interaction of neonatal MDSCs with adult macrophages to capture the full antibacterial potential of macrophages and subsequently assess the effect of MDSCs. A second advantage to this approach is that it minimizes the influence of macrophage‐derived IL‐27 and allows for a better dissection of the impact of MDSC‐derived IL‐27 since adult macrophages produce significantly less cytokine relative to neonates . E. coli is a leading cause of neonatal sepsis .…”

“…Another important finding reported in this work was that the above observations manifest as higher levels of IL‐27 circulating in serum of neonatal animals. We previously reported peak IL‐27 levels in the spleen in the second and third weeks of life . Although speculative, the peak level of IL‐27 in serum the first week of life could be explained by a shift from MDSCs as the dominant producer of IL‐27 early to macrophages as the dominant producer in subsequent weeks.…”

“…In our previous report, monocyte‐derived macrophages from cord blood were shown to express genes that comprise IL‐27 at elevated levels compared with that of cellular counterparts from adult blood . This manifests as increased secretion of IL‐27 in culture supernatants . In mice, expression of the Epstein–Barr virus‐induced gene 3 is increased in spleens from mice in the first week of life and maintained at a high level through 21 days of life before declining into adulthood .…”