Role of TNF-[alpha] in the mechanisms responsible for preterm delivery induced by Stx2 in rats

• Published in: British journal of pharmacology 2013-02, Vol.168 (4), p.946
• Main Authors: Burdet, Juliana, Sacerdoti, Flavia, Cella, Maximiliano, Franchi, Ana M, Ibarra, Cristina
• Format: Article
• Language: English
• Subjects: Birth weight; Premature birth
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2012.02239.x

Background and Purpose Infections with a strain of Escherichia coli producing Shiga toxins could be one of the causes of fetal morbidity and mortality in pregnant women. We have previously reported that Shiga toxin type 2 (Stx2) induces preterm delivery in pregnant rats. In this study, we evaluate the role of TNF-[alpha], PGs and NO in the Stx2-induced preterm delivery. Experimental Approach Pregnant rats were treated with Stx2 (0.7ngg-1) and killed at different times after treatment. Placenta and decidua were used to analyse NOS activity by the conversion of L-[14C]arginine into L-[14C]citrulline, levels of PGE2 and PGF2[alpha] assessed by radioimmunoassay, and cyclooxygenase (COX) proteins by Western blot. TNF-[alpha] level was analysed in serum by ELISA and by cytotoxicity in L929 cells. The inhibitor of inducible NOS, aminoguanidine, the COX-2 inhibitor, meloxicam, and the competitive inhibitor of TNF-[alpha], etanercept, were used alone or combined to inhibit NO, PGs and TNF-[alpha] production respectively, to prevent Stx2-induced preterm delivery. Key Results Stx2 increased placental PGE2 and decidual PGF2[alpha] levels as well as COX-2 expression in both tissues. Aminoguanidine and meloxicam delayed the preterm delivery time but did not prevent it. Etanercept blocked the TNF-[alpha] increase after Stx2 treatment and reduced the preterm delivery by approximately 30%. The combined action of aminoguanidine and etanercept prevented Stx2-induced preterm delivery by roughly 70%. Conclusion and Implications Our results demonstrate that the increased TNF-[alpha] and NO induced by Stx2 were the predominant factors responsible for preterm delivery in rats. [PUBLICATION ABSTRACT]