Role of TNF-α in the Mechanisms Responsible for Preterm Delivery Induced by Stx2 in Rats

BURDET, JULIANA; SACERDOTI FLAVIA; CELLA, MAXIMILIANO; FRANCHI, ANA MARIA; IBARRA, CRISTINA

BRITISH JOURNAL OF PHARMACOLOGY

WILEY-BLACKWELL PUBLISHING, INC

Lugar: Londres; Año: 2013 vol. 168 p. 946 - 953

0007-1188

BACKGROUND AND PURPOSE. Shiga toxin-producing Escherichia coli (STEC)infections could be one of the causes of fetal morbimortality in pregnant women. Wehave previously reported that Shiga toxin type 2 (Stx2) causes preterm delivery inpregnant rats. In this study, we evaluate the role of tumor necrosis factor alpha (TNF-α),prostaglandins (PGs), and nitric oxide (NO) in the Stx2induced preterm delivery.EXPERIMENTAL APPROACH. Pregnant rats were treated with 0.7 ng Stx2/g of bodyweight and killed at different times after treatment. Placenta and decidua were used toanalyze NO synthase (NOS) activity by conversion L-[14C]arginine into L-[14C]citruline,PGE2 and PGF2α by radioimmunoassay, and cyclooxygenases (COX) protein byWestern blot. TNF-α level was analyzed in serum by ELISA and by L929 cytotoxicity.Aminoguanidine (AG, inducible NOS inhibitor), meloxicam (Melo, COX-2 inhibitor) andetanercept (ETA, competitive inhibitor of TNF-α) were used alone or combined to inhibitNO, PGs and TNF-α production respectively, to prevent Stx2-induced preterm delivery.KEY RESULTS. Stx2 increased placental PGE2 and decidual PGF2α levels as well asCOX-2 expression in both tissues. AG and Melo delayed the preterm delivery time butdid not prevent it. ETA blocked the TNF-α increase after Stx2 treatment and reducedthe preterm delivery by approximately 30%. The combined action of AG and ETAprevented Stx2-induced preterm delivery by roughly 70 %.CONCLUSIONS AND IMPLICATIONS. Our results demonstrate for the first time thatthe increase of TNF-α and NO produced by Stx2 are mostly responsible for the pretermdelivery in rats.