Co-expression of activating and inhibitory receptors on peritoneal fluid NK cells in women with endometriosis.

The detailed mechanism underlying endometriosis development remains unclear; few reports have suggested the involvement of immune and genetic factors. This study aims to investigate the role of NK cells in endometriosis by analyzing the co-expression of activating (NKp46, NKG2C, and NKG2D) and inhibitory receptors (NKG2A and CD158a) on NK cells and their subsequent cytokine production in the peritoneal fluid (PF). Sixty-two patients were enrolled for this study from Hyogo Medical University between February 2018 and April 2022. Results showed that the proportions of CD56+/NKp46+, CD56dim/NKp46＋, NKG2C＋/NKp46＋, and NKG2D＋/NKp46＋ NK cells were significantly lower in the endometriosis group than those in the control group. Meanwhile, within the peritoneal endometriosis (n = 21) and deep infiltrating endometriosis (n = 11) groups, the co-expression of NKG2D＋/NKp46＋ and CD16＋/NKp46＋. Additionally, the abundance of IFN-γ-producing NK cells was significantly increased in the endometriosis group compared to controls, and a significant negative correlation was noted between NKp46 expression on NK cells and type 1 cytokine (IFN-γ and TNF-α) production. Taken together, the findings of this study indicate that NK cell cytotoxicity in endometriosis is reduced due to changes in NKp46 expression, as well as activating receptors co-expressed with NKp46. Consequently, NK cells do not eliminate endometrial cells in the abdominal cavity, resulting in the production of TNF-α and IFN-γ.

NK cells that differ in expression of NKp46 might play different roles in endometrium.

NKp46 is a natural cytotoxicity receptor expressed by NK cells and its expression is decreased in reproductive failure patients. NKp46 can be subdivided into NKp46dim and NKp46bright according to different fluorescence staining intensities. We investigated the role of the NKp46 receptor in determining the reproductive outcomes. Uterine endometrium was collected from 34 women with reproductive failure and divided into the pregnant and failed groups based on the results of a pregnancy reaction test during a 1-year follow-up period. NKp46 receptor and other activating or inhibitory receptors expressed on NK cells as well as intracellular cytokine production by NK cells were analyzed by multicolor flow cytometry. In the failed group, the percentage of NKp46dim NK cells (P < 0.05) was significantly higher and percentages of NKp46bright NK cells (P < 0.01) and CD16-/CD56bright NK cells (P < 0.05) were significantly lower than those in the pregnant group. NKp46dim NK cells were significantly and positively correlated with CD16+/NKp46dim NK cells; NKp46bright NK cells were significantly and positively correlated with CD16-/NKp46bright NK cells. CD16+/NKp46dim NK cells were significantly and positively correlated with IFN-γ- and/or TNF-α-producing NK cells; CD16-/NKp46bright NK cells were significantly and positively correlated with TGF-ß1-producing NK cells. We suggest that the NKp46 receptor plays different roles in reproduction based on the different fluorescence intensities associated with NK cells, i.e. NKp46dim NK cells are involved in killing cells, whereas NKp46bright NK cells are involved in cytokine production, indicating that NKp46 could be a predictive marker to see a tolerate condition for embryos.

Co-expression of NKp46 with activating or inhibitory receptors on, and cytokine production by, uterine endometrial NK cells in recurrent pregnancy loss.

NKp46 (CD335) is one of the activating receptors expressed on NK cells and its expression is decreased in patients with reproductive failure. However, the reasons remain unknown. In this study, we aimed to clarify the significance of decreased NKp46 expression in reproductive failure. Uterine endometrial samples collected from 39 patients with recurrent pregnancy loss (RPL) were assigned to high- or low-risk groups based on an 18 % ratio of CD16+/CD56dim NK cells in uterine endometrial NK (uNK) cells. We analyzed the expression of NKp46 and other activating or inhibitory receptors on, and intracellular cytokine production by NK cells using multicolor flow cytometry. The numbers of NKp46+/CD16- NK, NKp46+/NKG2C- NK, IL-4+/CD56+ NK, and IL-10+/CD56+ NK cells were significantly decreased, whereas that TNF-α+/CD56+ NK cells was significantly increased in the high-risk group, when compared with the low-risk group (P < 0.05 for all). The ratios of TNF-α/IL-4, IFN-γ/IL4, TNF-α/IL-10, and IFN-γ/IL10 cytokine production in uNK cells were significantly increased in the high-risk when compared with the low-risk group (P < 0.05, for all). It is suggested that low expression of activating receptors on NKp46 uNK cells is more prevalent in high-risk women.

Pelvic endometriosis and natural killer cell immunity.

Endometriosis is a chronic disease that commonly affects women in their reproductive age. It has been reported that the infertility due to endometriosis is largely caused by pelvic adhesion, oocyte damage, and so on. There are several causes of endometriosis including bacterial infections, immunological abnormalities, epigenetics, and aberrant DNA methylation. The natural killer (NK) cells present in the peritoneal fluid express CD16 and CD56. They also express NK cell inhibitory receptors and activating receptors and usually work to eliminate endometrial cells in the retrograde menstruation. However, in women with endometriosis, the changes in these receptors and production of cytokines by NK cells cause the onset and progression of endometriosis. In this review, we have focused on the role of NK cells in pelvic endometriosis and presented the immunological abnormalities in endometriosis including the possibility of future treatment.

Itraconazole Inhibits AKT/mTOR Signaling and Proliferation in Endometrial Cancer Cells.

BACKGROUND: Itraconazole is a common antifungal agent that has demonstrated anticancer activity in preclinical and clinical studies. This study investigated whether itraconazole exerts this effect in endometrial cancer (EC) cells. MATERIALS AND METHODS: Cell viability was evaluated with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and gene and protein expression were assessed by microarray analysis and immunoblotting, respectively, in five EC cell lines. RESULTS: Itraconazole-suppressed proliferation of AN3-CA, HEC-1A and Ishikawa cells (p<0.05) but not of HEC-50B or SNG-II cells. Itraconazole did not suppress GLI1 or GLI2 transcription but did inhibit the expression of mammalian target of rapamycin (mTOR) signaling components in AN3-CA and HEC-1A cells, while inducing that of microtubule-associated protein 1A/1B-light chain 3-II, a marker of autophagy. ATP-binding cassette transporter A1 gene was down-regulated in Ishikawa, HEC-50B and SNG-II cells. CONCLUSION: Itraconazole treatment suppresses the growth of EC cells by inhibiting AKT/mTOR signalling.

Benefit of palliative chemotherapy and hospice enrollment in late-stage ovarian cancer patients.

AIM: The ideal timing for transition to best supportive care (BSC) for ovarian cancer patients is not clear. We retrospectively assessed the survival benefit of continuing chemotherapy and hospice enrollment in late-stage ovarian cancer patients. MATERIALS AND METHODS: Eligibility criteria included platinum and taxane treatment, clinical progression within 6 months of the last platinum dose, and progression during chemotherapy. RESULTS: Of the 55 eligible patients (median overall survival after first becoming refractory [1st Ref], 96 days), 22 received chemotherapy (Chemo group), two received radiation therapy, and 13 had medical contraindications for subsequent chemotherapy. The remaining 18 patients (BSC group) were compared with the Chemo group. The Chemo and BSC groups had similar background characteristics, except for the rate of consultation with a regional palliative care physician before or within 1 week of 1st Ref (9% vs 50%, respectively). In multivariate analysis, chemotherapy (hazard ratio 0.251, P = 0.005) and hospice enrollment (hazard ratio, 0.274, P = 0.023) were predictive factors of survival after 1st Ref. CONCLUSIONS: Chemotherapy after 1st Ref can be offered and hospice enrollment during the terminal stages is encouraged for recurrent ovarian cancer patients.