Figure 12.

Proposed mechanism for protease amplification of the inflammatory response induced by commensal bacteria that could trigger the onset of labor. Commensal bacteria present in decidual tissue stimulate resident macrophages to release proteases that act in an autocrine manner to amplify the response by activating PAR-1 on adjacent macrophages and other decidual leukocytes that express PAR-1. Activation of PAR-1 leads to down-stream signaling to ROCK that phosphorylates TET2 and NF-κB causing their translocation from the cytosol to the nucleus. In the nucleus, TET2 enzymatically de-methylates DNA opening up transcription factor binding sites for NF-κB resulting in increased expression of inflammatory genes to initiate labor. Commensal bacteria tested were L. crispatus, which is prevalent in the vaginal microbiome of women of European ancestry, and L. iners and F. nucleatum, which are prevalent in the vaginal microbiome of African-American women. We observed a more robust inflammatory response for L. iners and F. nucleatum than for L. crispatus which might explain the higher incidence of PTB in African-Americans, however commensal bacteria may be the initiators of labor in both term and preterm labor.