Interleukin-10: a pleiotropic regulator in pregnancy

Abstract

Pregnancy is a unique and well-choreographed physiological process that involves intricate interplay of inflammatory and anti-inflammatory milieu, hormonal changes, and cellular and molecular events at the maternal-fetal interface. IL-10 is a pregnancy compatible cytokine that plays a vital role in maintaining immune tolerance. A wide array of cell types including both immune and non-immune cells secret IL-10 in an autocrine and paracrine manner. IL-10 binds to a specific receptor complex and activates JAK-STAT and PI3K-Akt signaling pathways while inhibiting NF-κB signaling pathway. IL-10 exerts its anti-inflammatory effects mainly by decreasing pro-inflammatory cytokines such as IL-1, IL-6, IL-12, and TNF-α, by inducing heme oxygenase-1, and by inhibiting antigen presentation via blocking major histocompatibility complex (MHC) class II expression. Prior studies from our group and others have shown that IL-10 also functions as a potent protector against vascular dysfunction, and enhancement of IL-10 may serve as an immunotherapeutic intervention to treat adverse pregnancy outcomes. This review seeks to critically evaluate the archetypal functions of IL-10 as an immune suppressive factor as well as its novel functions as a vascular protector and modulator of endoplasmic reticulum (ER) stress and autophagy in the context of normal and adverse pregnancy outcomes.

Keywords: Adverse pregnancy outcomes; angiogenesis; autophagy; endoplasmic reticulum stress; immune tolerance; preeclampsia.

Figure 1

Role of IL-10 in adverse pregnancy outcomes. IL-10 deficiency coupled with other insults including hypoxia, bacterial and viral infection as well as inflammatory triggers disturbs the balance between anti-inflammation and pro-inflammation at the maternal-fetal interface and consequently results in placental ER stress, inflammation and apoptosis as well as release of anti-angiogenic factors. As a result, maternal immune tolerance and vascular remodeling are perturbed, leading to many adverse pregnancy outcomes.

Figure 2

IL-10 signaling pathways in normal and abnormal conditions. Binding of IL-10 to its specific receptor complex (IL-10R1 and IL-10R2) leads to activation of several signaling pathways, including well-established Jak/STAT pathway, PI3K/Akt- and P38/MAPK-mediated pathways, as well as CO-mediated pathway. Through its signal transduction, IL-10 plays a role in anti-inflammation, vascular protection and inhibition of ER stress and autophagy.