The effects of lipopolysaccharide and interleukins-1alpha, -2 and -6 on oxytocin receptor expression and prostaglandin production in bovine endometrium

Abstract

Up-regulation of endometrial oxytocin receptor (OTR) expression followed by an increase in pulsatile endometrial prostaglandin (PG) F 2 secretion causes luteolysis in cattle. Inhibition of luteolysis is essential for the maternal recognition of pregnancy but also occurs in association with endometritis. The factors regulating OTR expression at this time are unclear. The OTR gene promoter region contains binding elements for acute phase proteins but their function has not been established. This study investigated the effects of various cytokines on OTR expression and on PGF 2 and PGE 2 production in explant cultures of bovine endometrium. Endometrium was collected in the late luteal phase (mean day of cycle 15·4 0·50) or early luteolysis (mean day of cycle 16·4 0·24) as determined by the initial concentration of endometrial OTR. Explants were treated for 48 h with: (i) lipopolysaccharide (LPS) and/or dexamethasone (DEX), (ii) ovine interferon-tau (oIFN-), or (iii) human recombinant interleukin (IL)-1 , -2 or -6. OTR mRNA was then measured in the explants by in situ hybridisation and the medium was collected for measurement of PGF 2 and PGE 2 by RIA. LPS treatment stimulated production of PGF 2 , whereas DEX either alone or in combination with LPS was inhibitory to both PGF 2 and PGE 2 . Neither of these treatments altered OTR mRNA expression. oIFN-reduced OTR mRNA expression but stimulated production of both PGF 2 and PGE 2 . In endometrial samples collected in the late luteal phase, IL-1 , -2 and -6 all inhibited OTR mRNA expression, but IL-1 and -2 both stimulated PGF 2 production. In contrast, when endometrium was collected in early luteolysis, none of the interleukins altered OTR expression or caused a significant stimulation of PGF 2 production but IL-2 increased PGE 2 . Neither IL-1 nor -2 altered OTR promoter activity in Chinese hamster ovary cells transfected with a bovine OTR promoter/chloramphenicol acetyl transferase reporter gene construct. In conclusion, the action of interleukins on both OTR mRNA expression and endometrial prostaglandin production alters around luteolysis. Pro-inflammatory interleukins suppress OTR expression in the late luteal phase, while LPS stimulates PGF 2 without altering OTR mRNA expression. IL-I and -2 and LPS are therefore unlikely to initiate luteolysis but may cause raised production of PGF 2 during uterine infection.

Is interleukin-1α a luteotrophic or luteolytic agent in cattle?

“…Only at a dose of 10 mg did IL1A increase temporally PGFM plasma concentration without effecting P 4 secretion and CL lifespan. These findings agree with data of Leung et al (2001) showing that proinflammatory ILs suppress OXTR expression in the late luteal phase. The cytokines IL1 and IL2 are therefore unlikely to initiate/modulate luteolysis.…”

“…Previous results suggest that stromal cells are the target of IL1A and IL1B for stimulating the production of both PGs (Tanikawa et al 2008). The action of IL1 and IL2 on both OXT receptor (OXTR) mRNA expression and endometrial PG production may alter luteolysis (Leung et al 2001). Recent in vitro studies from our laboratory suggest that IL1A plays some role in regulating the PGF 2a to PGE 2 ratio during the estrous cycle, and that this effect is mediated via regulation of PGE synthase (Tanikawa et al 2005(Tanikawa et al , 2008.…”

“…The mRNAs for IL1A and IL1B (IL1b) and receptor IL1R are present in the bovine CL and endometrium throughout the estrous cycle (Nishimura et al 2004, Tanikawa et al 2005 and during early pregnancy (Leung et al 2000). In vitro studies suggest that ILs act as local modulators of both luteolytic PGF 2a and luteotrophic PGE 2 production in the bovine CL and endometrium (Betts & Hansen 1992, Leung et al 2001, Nishimura et al 2004, Tanikawa et al 2005.…”

“…Recent in vitro studies from our laboratory suggest that IL1A plays some role in regulating the PGF 2a to PGE 2 ratio during the estrous cycle, and that this effect is mediated via regulation of PGE synthase (Tanikawa et al 2005(Tanikawa et al , 2008. However, based on in vitro studies, there is no consensus whether IL1A has luteotrophic or luteolytic properties (Betts & Hansen 1992, Leung et al 2001, Tanikawa et al 2005. Therefore, to determine the physiological role of IL1A during the estrous cycle and early pregnancy in cows, we examined the influence of IL1A on PG secretion by cultured bovine endometrial tissues obtained from cyclic or early pregnant cows (days 16-17).…”

The effect of a diet supplemented with the n-6 polyunsaturated fatty acid linoleic acid on prostaglandin production in early- and late-pregnant ewes

“…Strips of each tissue were placed in basic Dulbecco's modified Eagle's medium (DMEM)/Ham's F12 medium (Gibco Life Technologies, Paisley, UK) containing 1·125 g/l fatty acid-free BSA and antibiotics (50 000 units/l penicillin and 50 mg/l streptomycin). The method for explant culture has been described previously (Leung et al 2001). Strips of IC and allantochorion tissue were chopped into 1 mm 3 cubes.…”