title: Role of TNF-α in the mechanisms responsible for preterm delivery induced by Stx2 in rats.
abstract: OBJECTIVE
  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-α, PGs and NO in the Stx2-induced preterm delivery.
  
  
  METHODS
  Pregnant rats were treated with Stx2 (0.7 ng g(-1)) and killed at different times after treatment. Placenta and decidua were used to analyse NOS activity by the conversion of L-[(14)C]arginine into L-[(14)C]citrulline, levels of PGE(2) and PGF(2α) assessed by radioimmunoassay, and cyclooxygenase (COX) proteins by Western blot. TNF-α 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-α, etanercept, were used alone or combined to inhibit NO, PGs and TNF-α production respectively, to prevent Stx2-induced preterm delivery.
  
  
  RESULTS
  Stx2 increased placental PGE(2) and decidual PGF(2α) 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-α 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%.
  
  
  CONCLUSIONS
  Our results demonstrate that the increased TNF-α and NO induced by Stx2 were the predominant factors responsible for preterm delivery in rats.
authors.affiliation: Laboratorio de Fisiopatogenia, Departamento de Fisiología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Juliana
authors.initials: J
authors.lastname: Burdet
authors.forename: Flavia
authors.initials: F
authors.lastname: Sacerdoti
authors.forename: Maximiliano
authors.initials: M
authors.lastname: Cella
authors.forename: Ana M
authors.initials: AM
authors.lastname: Franchi
authors.forename: Cristina
authors.initials: C
authors.lastname: Ibarra
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D003656:Decidua / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D015237:Dinoprost / Q000096:biosynthesis*; D015232:Dinoprostone / Q000096:biosynthesis*; D004359:Drug Therapy, Combination; D000068800:Etanercept; D005260:Female; D006146:Guanidines / Q000008:administration & dosage / Q000627:therapeutic use; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000627:therapeutic use; D009569:Nitric Oxide / Q000096:biosynthesis; D010920:Placenta / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D011247:Pregnancy; D047928:Premature Birth / Q000097:blood / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage / Q000627:therapeutic use; D022641:Shiga Toxin 2 / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood*
chemical_list: D006146:Guanidines; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D022641:Shiga Toxin 2; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D015237:Dinoprost; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D015232:Dinoprostone; D000068800:Etanercept; C004479:pimagedine