| The maternal immune mechanisms maintaining tolerance against the genetically foreign fetus remains a medical enigma. The toll-like receptor 4 (TLR4) regulates innate and adaptive immune responses to bacterial infection and tissue damage. A recent study in TLR4 mutant mice suggests a role in pregnancy maintenance. I hypothesized that pregnant women express low levels of TLR4, to prevent aggressive inflammatory responses. I compared TLR4 mRNA/protein levels in peripheral blood leukocytes of age-matched, pregnant women versus nonpregnant women. I saw over a two-fold lower expression in pregnant women.;The steroid hormones, glucocorticoids and progesterone, are markedly increased during pregnancy. Using a monocyte cell line, I found that both steroids significantly inhibited TLR4 expression. Experiments to determine the mechanism of regulation of TLR4 expression by these hormones involved co-treatments with the progesterone or glucocortocoid receptor blocker, RU486. I found that RU486 partially blocked the inhibition of TLR4 expression by glucocorticoids but not progesterone, suggesting that glucocorticoids mediate its effects by binding to its receptor. The stability of TLR4 mRNA was significantly decreased by progesterone, suggesting a role for post-transcriptional modification in the regulation of TLR4 gene expression. A plausible mechanism of TLR4 regulation by glucocorticoids is at the transcriptional level since the receptor is a known nuclear transcription factor. Glucocorticoids, and to a lesser extent progesterone, significantly inhibited TLR4 gene transcription. Promoter studies showed transcriptional regulation by glucocorticoids only when glucocorticoid receptor was present in the cell. Therefore, glucocorticoids appear to lower TLR4 expression in pregnancy by acting at the transcriptional level through its receptor.;To determine whether TLR4 expression is increased in preterm labor, since a maternal inflammatory response is a postulated factor, I compared TLR4 mRNA/protein levels in peripheral blood leukocytes of pregnant women versus women in preterm labor.;I found a markedly increased TLR4 mRNA expression in patients with preterm labor. In addition, TLR4 receptor density on monocytes was two fold higher in preterm labor.;This dissertation provides new insight into the mechanisms of maternal immune tolerance in pregnancy. Measuring maternal blood of TLR4 expression may offer a novel, minimally invasive approach to predict preterm labor. |
