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

Inflammation is a key feature of preterm and term labor. Proinflammatory mediators are produced by gestation-associated tissues in response to pathogen-associated molecular patterns and damage-associated molecular patterns. 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 proinflammatory cytokines produced by human term gestation-associated tissues (placenta, choriodecidua, and amnion). Both IL4 and IL13 reduced LPS-stimulated IL1B and macrophage inflammatory protein1A; this effect diminished with delay to exposure to either cytokine. There was no effect on LPS-stimulated prostaglandin production. Interleukin 4 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 downregulate LPS-induced cytokine production in these tissues. Antiinflammatory cytokines might offer an adjunct to existing therapeutics to prevent adverse obstetric outcome.