Suppression of autophagy and HCK signaling promotes PTGS2(high) FCGR3(-) NK cell differentiation triggered by ectopic endometrial stromal cells
AUTOPHAGY
Authors: Mei, Jie; Zhou, Wen-Jie; Zhu, Xiao-Yong; Lu, Han; Wu, Ke; Yang, Hui-Li; Fu, Qiang; Wei, Chun-Yan; Chang, Kai-Kai; Jin, Li-Ping; Wang, Jian; Wang, Yong-Ming; Li, Da-Jin; Li, Ming-Qing
Abstract
Impaired NK cell cytotoxic activity contributes to the local dysfunctional immune environment in endometriosis (EMS), which is an estrogen-dependent gynecological disease that affects the function of ectopic endometrial tissue clearance. The reason for the impaired cytotoxic activity of NK cells in an ectopic lesion microenvironment (ELM) is largely unknown. In this study, we show that the macroautophagy/autophagy level of endometrial stromal cells (ESCs) from EMS decreased under negative regulation of estrogen. The ratio of peritoneal FCGR3(-) NK to FCGR3(+) NK cells increases as EMS progresses. Moreover, the autophagy suppression results in the downregulation of HCK (hematopoietic cellular kinase) by inactivating STAT3 (signal transducer and activator of transcription 3), as well as the increased secretion of the downstream molecules CXCL8/IL8 and IL23A by ESCs, and this increase induced the upregulation of FCGR3(-) NK cells and decline of cytotoxic activity in ELM. This process is mediated through the depression of microRNA MIR1185-1-3p, which is associated with the activation of the target gene PTGS2 in NK cells. FCGR3(-) NK with a phenotype of PTGS2/COX2(high) IFNG(low) PRF1(low) GZMB(low) induced by hck knockout (hck(-/-)) or 3-methyladenine (3-MA, an autophagy inhibitor)-stimulated ESCs accelerates ESC's growth both in vitro and in vivo. These results suggest that the estrogen-autophagy-STAT3-HCK axis participates in the differentiation of PTGS2(high) IFNG(low) PRF1(low) GZMB(low) FCGR3(-) NK cells in ELM and contributes to the development of EMS. This result provides a scientific basis for potential therapeutic strategies to treat diseases related to impaired NK cell cytotoxic activity.
Interferon-gamma release assay performance in northeastern Brazil: influence of the IFNG+874 A > T polymorphism
BRAZILIAN JOURNAL OF INFECTIOUS DISEASES
Authors: Carneiro, Valdirene Leao; Bendicho, Maria Teresita; Santos, Rosalina Guedes; Casela, Marilda; Netto, Eduardo M.; Moraes Mota, Scarlet Torres; Araujo Pina, Iza Cristina; Nascimento, Roberto Meyer; Freire, Songeli Menezes; Barbosa, Theolis
Abstract
Introduction: Latent tuberculosis infection diagnosis based on the release of interferon-gamma in cultures of peripheral blood cells stimulated with Mycobacterium tuberculosis antigens has replaced the tuberculin skin test in many countries with low tuberculosis prevalence. The IFN-gamma( )production can be influenced by genetic polymorphisms, of which the IFNG + 874 (rs62559044) locus is the most studied. We investigated the possible influence of the IFNG + 874 A/T polymorphism on interferon-gamma test performance. Methods: Patients diagnosed with pulmonary tuberculosis (75), volunteers with positive tuberculin skin test (70) and healthy volunteers with negative tuberculin skin test and no history of contact with tuberculosis (57) were evaluated regarding the IFNG +874 genotype and the IFN-gamma levels in whole blood cultures performed using an interferon-gamma commercial kit (QuantiFERON-TB (R) Gold In-Thbe). Results: IFN-gamma production was not influenced by the IFNG + 874 genotype, regardless of antigen or mitogen-based stimulation, which suggests that other genes may influence IFN-gamma production in response to mycobacteria. The IFNG + 874 polymorphism was found to exert no influence over QFT-IT test sensitivity in our study. Conclusion: The IFNG + 874 polymorphism was not shown to influence QuantiFERON-TB (R) Gold In-Ribe test performance in an admixed population from northeastern Brazil. (C) 2018 Sociedade Brasileira de Infectologia. Published by Elsevier Editora Ltda.