Production and regulation of interleukin-1 family cytokines at the materno-fetal interface

Abstract

IL-1 family members regulate innate immune responses, are produced by gestation-associated tissues, and have a role in healthy and adverse pregnancy outcomes. To better understand their role at the materno-fetal interface we used a human tissue explant model to map lipopolysaccharide (LPS)-stimulated production of IL-1α, IL-1β, IL-18, IL-33, IL-1Ra, IL-18BPa, ST2 and IL-1RAcP by placenta, choriodecidua and amnion. Caspase-dependent processing of IL-1α, IL-1β, IL-18, and IL-33 and the ability of IL-1α, IL-1β, IL-18, and IL-33 to regulate the production of IL-1RA, IL-18BPa, ST2 and IL-1RAcP was also determined. LPS acted as a potent inducer of IL-1 family member expression especially in the placenta and choriodecidua with the response by the amnion restricted to IL-1β. Caspases-1, 4 and 8 contributed to LPS-stimulated production of IL-1β and IL-18, whereas calpain was required for IL-1α production. Exogenous administration of IL-1α, IL-1β, IL-18, and IL-33 lead to differential expression of IL-1Ra, IL-18BPa, ST2 and IL-1RAcP across all tissues examined. Most notable were the counter-regulatory effect of LPS on IL-1β and IL-1Ra in the amnion and the broad responsiveness of the amnion to IL-1 family cytokines for increased production of immunomodulatory peptides and soluble receptors. The placenta and membranes vary not only in their output of various IL-1 family members but also in their counter-regulatory mechanisms through endogenous inhibitory peptides, processing enzymes and soluble decoy receptors. This interactive network of inflammatory mediators likely contributes to innate defence mechanisms at the materno-fetal interface to limit, in particular, the detrimental effects of microbial invasion.

IL-1 receptor antagonist therapy mitigates placental dysfunction and perinatal injury following Zika virus infection

“…ZIKV is not the only exposure that causes IL-1βmediated inflammation during pregnancy. Previous studies employing intrauterine LPS have established that IL-1β-mediated inflammation in the maternal compartment and placenta predicts the extent of fetal neurotoxicity and long-term adverse perinatal sequelae (56)(57)(58)(59). Furthermore, IL-1 receptor blockade with IRA decreases activation of neuronal NOS (nNOS), cortical neuronal cell death, and perinatal brain injury, all of which occur with exposure to intrauterine inflammation (25,60,61).…”

Protective role of IL33 signaling in negative pregnancy outcomes associated with lipopolysaccharide exposure

“…IL33 and ST2 are expressed at the maternal-fetal interface. [31][32][33][34][35][36][37][38] Disruptions of IL33 signaling have been connected to diseases of pregnancy and placentation. Both recurrent pregnancy loss and preeclampsia are associated with aberrations in IL33 and/or ST2 function.…”

“…Both recurrent pregnancy loss and preeclampsia are associated with aberrations in IL33 and/or ST2 function. [31][32][33][34][35][36][37][38][39][40][41][42][43] Furthermore, IL33 signaling has been implicated as a regulator of intrauterine immune cell events at the end of gestation preceding parturition. 43 The majority of these observations are correlative and place IL33 and ST2 in a provocative position as a potential regulator of pivotal gestational events.…”

Associations between maternal plasma measurements of inflammatory markers and urinary levels of phenols and parabens during pregnancy: A repeated measures study

“…In the third anti-inflammatory finding, elevated EPB concentrations were associated with reduced IL-1β. Produced predominantly by macrophages, IL-1β is an integral product of inflammasomes, which are cytoplasmic protein complexes that elicit inflammatory responses, and of particular importance at the placental and fetal membranes (Romero et al, 2016;Scott et al, 2017). The inverse associations that we observed were drawn from linear mixed models of strictly main effect terms.…”