Progesterone plays a protective role in preventing inflammation and preterm delivery during pregnancy. However, the mechanism involved is unknown. Microbial product translocation from a permeable mucosa is demonstrated as a driver of inflammation. To study the mechanism of the protective role of progesterone during pregnancy, we investigated the effect of physiologic concentrations of progesterone on tight junction protein occludin expression and human gut permeabilityin vitroand systemic microbial translocation in pregnant womenin vivo. Plasma bacterial lipopolysaccharide (LPS), a representative marker ofin vivosystemic microbial translocation was measured. We found that plasma LPS levels were significantly decreased during 24 to 28 weeks of gestation compared to 8 to 12 weeks of gestation. Moreover, plasma LPS levels were negatively correlated with plasma progesterone levels but positively correlated with plasma tumor necrosis factor-alpha (TNF-α) levels at 8 to 12 weeks of gestation but not at 24 to 28 weeks of gestation. Progesterone treatment increased intestinal trans-epithelial electrical resistance (TEER) in primary human colon tissues and Caco-2 cellsin vitrothrough upregulating tight junction protein occludin expression. Furthermore, progesterone exhibited an inhibitory effect on nuclear factor kappa B (NF-κB) activation following LPS stimulation in Caco-2 cells. These results reveal a novel mechanism that progesterone may play an important role in decreasing mucosal permeability, systemic microbial translocation, and inflammation during pregnancy.

The role of natural killer (NK) cell function in HIV disease especially in the setting of long-term antiretroviral therapy (ART) and viral suppression is not fully understood. In the current study, we have investigated NK cell activation in healthy controls and aviremic ART-treated HIV+ subjects with different degrees of immune restoration. We performed a cross sectional study in 12 healthy controls and 24 aviremic ART-treated HIV-infected subjects including 13 HIV+ subjects with CD4+ T cells above 500 cells/μL defined as “immunologic responders” and 11 HIV+ subjects with CD4+ T cells below 350 cells/μL defined as “immunologic non-responders”. We analyzed NK cell number, subset, and activation by expression of CD107a and NKG2D and co-expression of CD38 and HLA-DR. NK cell-mediated cytotoxicity against uninfected CD4+ T cells was tested in vitro. We found that NK cell absolute number, percentage of NK cells, and percentage of NK cell subsets were similar in the three study groups. The increased NK cell activation was found predominantly in CD56dimCD16+ subset of immunologic non-responders but not immunologic responders compared to healthy controls. The activation of NK cells was inversely correlated with the peripheral CD4+ T cell count in HIV+ subjects, even after controlling for chronic T cell activation, sex, and age, potential contributors for CD4+ T cell counts in HIV disease. Interestingly, NK cells from immunologic non-responders mediated cytotoxicity against uninfected CD4+ T cells ex vivo. NK cells may play a role in blunted CD4+ T cell recovery in ART-treated HIV disease.