Document Detail


The CRTH2 agonist Pyl A prevents lipopolysaccharide-induced fetal death but induces preterm labour.
MedLine Citation:
PMID:  23374103     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We have previously demonstrated that the anti-inflammatory prostaglandin 15-deoxy-Δ 12,14-prostaglandin J(2) (15dPGJ(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. 15dPGJ(2) is an agonist of the second prostaglandin D(2) receptor, chemoattractant receptor homologous to the T helper 2 cell (CRTH2). In human T helper cells CRTH2 agonists induce the production of the anti-inflammatory interleukins IL-10 and IL-4. We hypothesized that CRTH2 is involved in the protective effect of 15dPGJ(2) in inflammation-induced preterm labour in the murine model. We therefore studied the effects of a specific small molecule CRTH2 agonist on preterm labour and pup survival. An intrauterine injection of lipopolysaccharide (LPS) was administered to CD1 mice at embryonic day 16, ± CRTH2 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 CRTH2 agonist on LPS-induced preterm labour, mice were allowed to labour spontaneously. Direct effects of the CRTH2 agonist on uterine contractility were examined ex vivo on contracting myometrial strips. The CRTH2 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 15dPGJ(2) is not via CRTH2 and therefore small molecule CRTH2 agonists are not likely to be beneficial for the prevention of inflammation-induced preterm labour.
Authors:
Lynne Sykes; Bronwen R Herbert; David A Macintyre; Emma Hunte; Sathana Ponnampalam; Mark R Johnson; Tiong G Teoh; Phillip R Bennett
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Immunology     Volume:  139     ISSN:  1365-2567     ISO Abbreviation:  Immunology     Publication Date:  2013 Jul 
Date Detail:
Created Date:  2013-06-14     Completed Date:  2013-08-19     Revised Date:  2014-07-01    
Medline Journal Info:
Nlm Unique ID:  0374672     Medline TA:  Immunology     Country:  England    
Other Details:
Languages:  eng     Pagination:  352-65     Citation Subset:  IM    
Copyright Information:
© 2013 John Wiley & Sons Ltd.
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MeSH Terms
Descriptor/Qualifier:
Animals
Anti-Inflammatory Agents / agonists,  metabolism
Brain / drug effects,  metabolism
Cytokines / metabolism
Disease Models, Animal
Female
Fetal Death / chemically induced*
Humans
Immunologic Factors / agonists,  metabolism
Inflammation
Lipopolysaccharides / administration & dosage*,  pharmacology
Mice
Myometrium / drug effects,  metabolism
Obstetric Labor, Premature / chemically induced*,  immunology,  prevention & control
Peptides / administration & dosage*
Pregnancy
Prostaglandin D2 / agonists,  analogs & derivatives,  metabolism
Receptors, Immunologic / agonists*,  genetics,  metabolism
Receptors, Prostaglandin / agonists*,  genetics,  metabolism
Chemical
Reg. No./Substance:
0/15-deoxy-delta(12,14)-prostaglandin J2; 0/Anti-Inflammatory Agents; 0/Cytokines; 0/Immunologic Factors; 0/Lipopolysaccharides; 0/Peptides; 0/Receptors, Immunologic; 0/Receptors, Prostaglandin; 0/prostaglandin D2 receptor; 97483-83-5/PYL(a); RXY07S6CZ2/Prostaglandin D2
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