Preterm birth remains one of the most important issues facing perinatal medicine 
today, with chronic inflammation and/or infection being the biggest etiological 
factor. The nucleotide oligomerization domain (NOD) intracellular molecules 
recognize a wide range of microbial products as well as other intracellular 
danger signals, thereby initiating inflammation through activation of nuclear 
factor KB (NFKB), a central regulator of the terminal processes of human labor 
and delivery. The aims of this study were to determine the effect of 1) human 
labor, proinflammatory cytokines, and bacterial endotoxin LPS on NOD1 and NOD2 
expression and 2) NOD1 and NOD2 activation on the expression of prolabor 
mediators in human fetal membranes and myometrium. NOD1 and NOD2 expression was 
significantly higher in fetal membranes and myometrium after spontaneous labor 
when compared to nonlaboring tissues. Bacterial endotoxin LPS and the 
proinflammatory cytokines TNF and IL1B significantly increased NOD2, but not 
NOD1, expression. Furthermore, LPS-induced NOD2 expression was decreased by the 
NFKB inhibitor BAY 11-7082. In both fetal membranes and myometrium, the NOD1 
ligand bacterial iE-DAP and the NOD2 ligand bacterial MDP significantly 
increased the expression and secretion of proinflammatory cytokines (IL6 and 
IL8), cyclooxygenase (PTGS2) expression and subsequent release of prostaglandins 
PGE2 and PGF2alpha, and the expression and activity of MMP9. The effects of 
these NOD1 and NOD2 ligands were mediated via NFKB, as 1) both iE-DAP and MDP 
significantly increased NFKB activation and 2) the NFKB inhibitor BAY 11-7082 
attenuated iE-DAP- and MDP-induced expression and secretion of prolabor 
mediators. In conclusion, NOD1 and NOD2 are increased in laboring fetal 
membranes and myometrium and with bacterial infection. Agonist activation of 
NOD1 and NOD2 by bacterial products leads to NFKB activation and transcription 
of NFKB induced prolabor genes. NOD1 and NOD2 may thus represent therapeutic 
targets for the treatment and/or management of preterm birth.