IL-10 was originally identified in mice as a product of Th2 T cells with potent suppressive effects on inflammatory Th1 responses.1
Recent observations have led to the identification of a family of IL-10-related cytokines that include IL-19, IL-20, IL-22, IL-24, and IL-26.2
Importantly, IL-10 elicits pleiotropic immune responses and is produced not only by immune cells but also a variety of non-immune cells including trophoblasts.3,4
IL-10 is the most potent immunosuppressive cytokine, and its deficiency is associated with autoimmune diseases and heightened susceptibility to inflammation in both humans and mice.5–7
On the other hand, its localized production supports neoplastic growth by suppressing tumor-ablating immune responses.8,9
Thus, dysregulation of IL-10 expression is a key pathogenic event in a wide spectrum of human diseases. Despite therapeutic and disease-associated functions, the mechanisms regulating IL-10 expression are incompletely understood, even in immune cells that produce large amounts of this cytokine.
There is increased IL-10 production at the maternal–fetal interface during normal gestation as part of the polarized, intrauterine, anti-inflammatory milieu. This local increase in IL-10 has been shown to be produced by placental trophoblast cells and decidual innate immune cells and is implicated in controlling pro-inflammatory activities of these cells and their cytokine products.4,10–13
This increased intrauterine IL-10 production is not accompanied by a similar increase in systemic production by peripheral blood mononuclear cells (PBMCs). We have previously shown that this immunoregulatory cytokine is temporally regulated in the human placenta with significant attenuation at term.4
Importantly, we and others have demonstrated poor placental IL-10 production in decidua and placental tissue from a variety of pregnancy complications including unexplained spontaneous abortion, preterm birth, and preeclampsia.12,14,15
On the other hand, human trophoblasts expressing toll-like receptors (TLRs) produce IL-10 when exposed to lipopolysaccharide (LPS), a ligand for TLR4, suggesting a fail-safe mechanism for heightened inflammation.16
Nonetheless, it is not clear whether pregnancy complications are associated with defective systemic IL-10 production or whether local attenuation of IL-10 production intrinsically or in response to infection/inflammation contributes to their pathogenesis. It is thus plausible that IL-10 expression may be differentially regulated in the placenta and in circulating immune cells.
Recent reports provide evidence for genetically mediated regulation of IL-10 production. Although several polymorphic changes have been identified in the IL-10 gene promoter, the three sites at the −1082, −819, and −592 positions have been best characterized for their regulatory influence.6,17–21
At the −1082 position, the GG allele is associated with significantly increased production of IL-10 compared to the AA or AG alleles. On the other hand, the CC allele at the −592 position is less active compared to AA allele. The IL-10 promoter ATA haplotype constituted of polymorphic changes at the −1082, −819, and −592 positions has been shown to be associated with lower IL-10 production in several studies.22
In this regard, although several common haplotypes of the IL-10 promoter have been associated with a spectrum of pathologic conditions, expression studies are still inconclusive and there are only limited studies in pregnant patients.
Given the importance and temporal production of IL-10 at the maternal–fetal interface and its variance with PBMCs, we undertook this study to compare the common IL-10 promoter haplotypes for their transcriptional activity in trophoblasts and monocytic cells. Our results suggest that the ATA haplotype leads to differential repression of IL-10 production in human trophoblasts, particularly under LPS-inducible conditions. These observations provide a mechanistic basis for the link between microbial infections, inflammation, reduced IL-10 production, and adverse pregnancy outcomes.