TLR2-dependent SOCS1 induction by Ureaplasma urealyticum attenuates IDO1 expression and amplifies chemokine production in human amniotic epithelial cells

Ureaplasma urealyticum is among the organisms most frequently recovered from the amniotic cavity during intra-amniotic infection. Using primary human amniotic epithelial cells, we found that IFN-γ–inducible IDO1 reduces the viable cell-associated burden of U. urealyticum , in part through tryptophan depletion, and that infection attenuates IFN-γ–induced IDO1 expression. This attenuation was mediated in part by TLR2-dependent induction of SOCS1, which reduced STAT1 activation and STAT1-dependent interferon-stimulated gene expression, and was reproduced to a lesser extent by heat-killed organisms. Reduced IDO1 activity lowered kynurenine, an endogenous ligand of the aryl hydrocarbon receptor (AhR), and the accompanying decrease in AhR activity was associated with increased CXCL8 and CXCL1 secretion; supplementing infected cells with kynurenine reduced chemokine release in an AhR-dependent manner. In a factorial analysis, TLR2 inhibition and kynurenine supplementation each lowered chemokine output, with TLR2 blockade producing the larger effect. Conditioned medium from infected cells increased neutrophil migration, adhesion and priming, with migration and respiratory-burst responses confirmed in primary human neutrophils. In fetal membranes from women with prelabour rupture of membranes, CXCL8 was higher in Ureaplasma -positive specimens and correlated with bacterial load. These findings indicate that TLR2-dependent SOCS1 induction attenuates IFN-γ–driven IDO1 expression in amniotic epithelium, and that the associated reduction in AhR activity acts alongside direct TLR2 signaling to amplify chemokine production. In human fetal membranes, both SOCS1 and CXCL8 expression were associated with bacterial load.