There is a strong association between
infection and prematurity; however, the underlying mechanisms remain largely unknown. Nod1 and Nod2 are intracellular
pattern recognition receptors that are activated by bacterial
peptides and mediate innate immunity. We previously demonstrated that human first-trimester trophoblasts express Nod1 and Nod2, which trigger
inflammation upon stimulation. This study sought to determine the expression and function of Nod1 and Nod2 in third-trimester trophoblasts, and to characterize the in vivo effects of Nod1 activation on pregnancy outcome. Human term placental tissues and isolated term trophoblast expressed Nod1, but not Nod2. Activation of Nod1 by its agonist, bacterial γ-D-glutamyl-meso-
diaminopimelic acid (
iE-DAP), in term trophoblast cultures induced a proinflammatory
cytokine profile, characterized by elevated levels of secreted
IL-6, GRO-α, and MCP-1, when compared with the control. However, these
cytokines were not upregulated in response to Nod2 stimulation with bacterial MDP. Administration of high-dose bacterial
iE-DAP to pregnant C57BL/6J mice on embryonic day 14.5 triggered preterm delivery within 24 h.
iE-DAP at a lower dose that did not induce prematurity, reduced
fetal weight, altered the
cytokine profile at the maternal-fetal interface, and induced fetal
inflammation. Thus, functional Nod1 is expressed by trophoblast cells across gestation and may have a role in mediating
infection-associated
inflammation and prematurity. This study demonstrates that
pattern recognition receptors, other than the TLRs, may be implicated or involved in
infection-associated
preterm labor.