Critical paracrine interactions between TNF-alpha and IL-10 regulate lipopolysaccharide-stimulated human choriodecidual cytokine and prostaglandin E2 production.
Increased production of PGs by gestational membranes is believed to be a principal initiator of term and preterm labor. Intrauterine infection is associated with an inflammatory response in the choriodecidua characterized by elevated production of cytokines and PGs. The precise physiological significance of enhanced choriodecidual cytokine production in the mechanism of preterm labor remains uncertain. These studies were undertaken to dissect the roles and regulation of endogenous cytokines in regulating PG production by human choriodecidua. We used LPS treatment of human choriodecidual explants as our model system. In choriodecidual explant cultures, LPS (5 microg/ml) induced a rapid increase in TNF-alpha production, peaking at 4 h. In contrast, IL-10, IL-1beta, and PGE2 production rates peaked 8, 12, and 24 h, respectively, after LPS stimulation. Immunoneutralization studies indicated that TNF-alpha was a primary regulator of IL-1beta, IL-10, and PGE2 production, while IL-1beta stimulated only PGE2 production. Neutralization of endogenous IL-10 resulted in increased TNF-alpha and PGE2 production. IL-10 treatment markedly decreased TNF-alpha and IL-1beta production, but had no effect on PGE2 production. Taken together, these results demonstrate that the effects of LPS on choriodecidual cytokine and PG production are modulated by both positive and negative feedback loops. In the setting of an infection of the intrauterine, TNF-alpha may be a potential target for treatment intervention; IL-10 could be one such therapeutic.
Sato
Timothy A
TA
Liggins Institute and Division of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand. t.sato@auckland.ac.nz
Keelan
Jeffrey A
JA
Mitchell
Murray D
MD
D000276:Adjuvants, Immunologic / Q000037:antagonists & inhibitors / Q000502:physiology; D002823:Chorion / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D046508:Culture Techniques; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000276:immunology; D003656:Decidua / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015232:Dinoprostone / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D019899:Paracrine Communication / Q000276:immunology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*
D000276:Adjuvants, Immunologic; D016207:Cytokines; D007106:Immune Sera; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015232:Dinoprostone