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The CRTH 2 agonist P yl A prevents lipopolysaccharide‐induced fetal death but induces preterm labour
Author(s) -
Sykes Lynne,
Herbert Bronwen R.,
MacIntyre David A.,
Hunte Emma,
Ponnampalam Sathana,
Johnson Mark R.,
Teoh Tiong G.,
Bennett Phillip R.
Publication year - 2013
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.12085
Subject(s) - agonist , endocrinology , lipopolysaccharide , medicine , contractility , inflammation , myometrium , prostaglandin , receptor , fetus , in vivo , prostaglandin e2 , biology , uterus , pregnancy , genetics , microbiology and biotechnology
Summary We have previously demonstrated that the anti‐inflammatory prostaglandin 15‐deoxy‐Δ 12,14‐prostaglandin J 2 (15d PGJ 2 ) delays inflammation‐induced preterm labour in the mouse and improves pup survival through the inhibition of nuclear factor‐κB ( NF ‐κB) by a mechanism yet to be elucidated. 15d PGJ 2 is an agonist of the second prostaglandin D 2 receptor, chemoattractant receptor homologous to the T helper 2 cell ( CRTH 2). In human T helper cells CRTH 2 agonists induce the production of the anti‐inflammatory interleukins IL ‐10 and IL ‐4. We hypothesized that CRTH 2 is involved in the protective effect of 15d PGJ 2 in inflammation‐induced preterm labour in the murine model. We therefore studied the effects of a specific small molecule CRTH 2 agonist on preterm labour and pup survival. An intrauterine injection of lipopolysaccharide ( LPS ) was administered to CD 1 mice at embryonic day 16, ± CRTH 2 agonist/vehicle controls. Mice were killed at 4.5 hr to assess fetal wellbeing and to harvest myometrium and pup brain for analysis of NF ‐κB, and T helper type 1/2 interleukins. To examine the effects of the CRTH 2 agonist on LPS ‐induced preterm labour, mice were allowed to labour spontaneously. Direct effects of the CRTH 2 agonist on uterine contractility were examined ex vivo on contracting myometrial strips. The CRTH 2 agonist increased fetal survival from 20 to 100% in LPS ‐treated mice, and inhibited circular muscle contractility ex vivo . However, it augmented LPS ‐induced labour and significantly increased myometrial NF ‐κB, IL ‐1β, KC ‐ GRO , interferon‐γ and tumour necrosis factor‐α. This suggests that the action of 15d PGJ 2 is not via CRTH 2 and therefore small molecule CRTH 2 agonists are not likely to be beneficial for the prevention of inflammation‐induced preterm labour.