Cooperative effects of sequential [PGF.sub.2[alpha]] and IL-1[beta] on IL-6 and COX-2 expression in human myometrial cells

• Published in: Biology of reproduction 2019-05, Vol.100 (5), p.1370
• Main Authors: Leimert, Kelycia B, Verstraeten, Barbara S.E, Messer, Angela, Nemati, Rojin, Blackadar, Kayla, Fang, Xin, Robertson, Sarah A, Chemtob, Sylvain, Olson, David M
• Format: Article
• Language: English
• Subjects: Cesarean section; Cytokines; EDTA; Inflammation; Interleukin-1; Interleukins; Messenger RNA; Myometrium; Penicillin G; Physiological aspects; Pregnancy; Prostaglandins; Proteins; RNA; Smooth muscle; Women
• ISSN: 0006-3363
• DOI: 10.1093/biolre/ioz029

The change from the state of pregnancy to the state of parturition, which we call uterine transitioning, requires the actions of inflammatory mediators and results in an activated uterus capable of performing the physiology of labor. Interleukin (IL)-1[beta] and prostaglandin (PG)F2[alpha] are two key mediators implicated in preparing the uterus for labor by regulating the expression of uterine activation proteins (UAPs) and proinflammatory cytokines and chemokines. To investigate this process, primary human myometrial smooth muscle cells (HMSMC) isolated from the lower segment of women undergoing elective cesarean sections at term (not in labor) were used to test the inflammatory cytokine and UAP outputs induced by [PGF.sub.2[alpha]] and IL-1[beta] alone or in sequential combinations. [PGF.sub.2[alpha]] and IL-1[beta] regulate mRNA abundance of the [PGF.sub.2[alpha]] receptor FP, the IL-1 receptor system, interleukin 6, and other UAPs (OXTR, COX2), driving positive feedback interactions to further amplify their own proinflammatory effects. Sequential stimulation of HMSMC by [PGF.sub.2[alpha]] and IL-1[beta] in either order results in amplified upregulation of IL-6 and COX-2 mRNA and protein, compared to their effects individually. These profound increases were unique to myometrium and not observed with stimulation of human fetal membrane explants. These results suggest that [PGF.sub.2[alpha]] and IL-1[beta] act cooperatively upstream in the birth cascade to maximize amplification of IL-6 and COX-2, to build inflammatory load and thereby promote uterine transition. Targeting [PGF.sub.2[alpha]] or IL-1[beta], their actions, or intermediates (e.g. IL-6) would be an effective therapeutic intervention for preterm birth prevention or delay. Summary Sentence [PGF.sub.2[alpha]] and IL-1[beta] act cooperatively upstream in the birth cascade to maximize amplification of IL-6 and COX-2, contributing to increased inflammatory burden and promoting uterine transition. Key words: myometrium, cytokines, prostaglandins, amplification, parturition, inflammation.