Interleukin-4 and interleukin-13 down-regulate the lipopolysaccharide-mediated inflammatory response by human gestation-associated tissues

Inflammation is a key feature of preterm and term labour. Pro-inflammatory mediators are produced by gestation-associated tissues in response to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Interleukin (IL)4, IL10 and IL13 are anti-inflammatory cytokines with potential as anti-inflammatory therapies to prevent preterm birth. The objective of this study was to determine if IL4 and IL13 exert anti-inflammatory effects on lipopolysaccharide (LPS)-stimulated production of pro-inflammatory cytokines produced by human term gestation-associated tissues (placenta, choriodecidua and amnion). Both IL4 and IL13 reduced LPS-stimulated IL1B and macrophage inflammatory protein (MIP)1A; this effect diminished with delay to exposure to either cytokine. There was no effect on LPS-stimulated prostaglandin production. IL4 receptor alpha (IL4RA) was expressed throughout the placenta, choriodecidua and amnion, and the inhibitory effects of IL4 and IL13 were IL4RA-dependent. Combined IL4 and IL13 did not enhance the anti-inflammatory potential of either cytokine; however, a combination of IL4 and IL10 had a greater anti-inflammatory effect than either cytokine alone. These findings demonstrate that human term gestation-associated tissues are responsive to the anti-inflammatory cytokines IL4 and IL13, which could down-regulate LPS induced cytokine production in these tissues. Anti-inflammatory cytokines might offer an adjunct to existing therapeutics to prevent adverse obstetric outcome.