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IFN-? induces aberrant CD49b? NK cell recruitment through regulating CX3CL1: a novel mechanism by which IFN-? provokes pregnancy failure.

ABSTRACT: Interferon-? (IFN-?), a pleiotropic lymphokine, has important regulatory effects on many cell types. Although IFN-? is essential for the initiation of uterine vascular modifications and maintenance of decidual integrity, IFN-? administration can also cause pregnancy failure in many species. However, little is known about the effector mechanisms involved. In this study, using an IFN-?-induced abortion mouse model, we reported that no Dolichos biflorus agglutinin lectin-positive uterine natural killer (uNK) cells were observed in the uteri from IFN-?-induced abortion mice. By contrast, the percentage of CD3(-)CD49b(+) NK cells in the uterus and blood from a foetal resorption group was significantly higher than that of the control group. Similarly, significantly upregulated expression of CD49b (a pan-NK cell marker), CX3CL1 and CX3CR1 (CX3CL1 receptor) was detected in the uteri of IFN-?-induced abortion mice. Using isolated uterine stromal cells, we showed that upregulated expression of CX3CL1 by IFN-? was dependent on a Janus family kinase 2-signal transducers and activators of transcription 1 (JAK2-STAT1) pathway. We further demonstrated the chemotactic activity of CX3CL1 in uterine stromal cell conditioned medium on primary splenic NK cells. Finally, we observed increased recruitment of CD49b(+) NK cells into the endometrium after exogenous CX3CL1 administration. Collectively, our findings indicate that IFN-? can significantly increase uterine CX3CL1 expression via activation of the JAK2-STAT1 pathway, thus inducing CD49b(+) NK cell uterine homing, and eventually provoke foetal loss. Thus, we provide a new line of evidence correlating the deleterious effects of IFN-? on pregnancy with the aberrant regulation of CX3CL1 and CD49b(+) NK cells.

SUBMITTER: Li ZY

PROVIDER: S-EPMC4260728 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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IFN-γ induces aberrant CD49b⁺ NK cell recruitment through regulating CX3CL1: a novel mechanism by which IFN-γ provokes pregnancy failure.

Li Z-Y ZY Chao H-H HH Liu H-Y HY Song Z-H ZH Li L-L LL Zhang Y-J YJ Yang Y Y Peng J-P JP

Cell death & disease 20141106

Interferon-γ (IFN-γ), a pleiotropic lymphokine, has important regulatory effects on many cell types. Although IFN-γ is essential for the initiation of uterine vascular modifications and maintenance of decidual integrity, IFN-γ administration can also cause pregnancy failure in many species. However, little is known about the effector mechanisms involved. In this study, using an IFN-γ-induced abortion mouse model, we reported that no Dolichos biflorus agglutinin lectin-positive uterine natural ki ...[more]

PMID: 25375377

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Project description:BackgroundAs part of the internal pilot of the EMPOWER trial investigating the second-line antiemetic therapies in severe emesis in pregnancy ( https://www.isrctn.com/ISRCTN16924692 ), a qualitative study of women's views was carried out, to improve our understanding of why women did, or did not, consent to participation in the trial. Interviews were also conducted with site research staff, to broaden our analysis and explore other factors affecting recruitment.MethodsThe sample comprised women who accepted or declined trial participation (n=21) and site research staff (n=22). A structured topic guide was used, in four email interviews and 17 telephone interviews with women, and semi-structured telephone interviews were carried out with staff. Of the women interviewed, seven had declined trial participation, and of the staff interviewed, 16 were research midwives/research nurses and six were principal investigators. All transcripts were checked for accuracy, anonymised and entered into NVIVO12 for indexing and retrieval. Data was analysed using a reflexive thematic analytic approach. In total, 72 codes were generated from the thematic analysis, and 36 from each sample group.ResultsThree key themes based on all the interviews were (a) the diversity of recruitment pathways and boundaries of care, (b) the impact of trial complexity on recruitment and staff morale and (c) the ethics of caring for a patient with emesis. Ethical issues discussed included the use of double dummy and time to treat, particularly those suffering severely from the effects of nausea and vomiting. To illustrate these themes, staff perspectives are given more prominence.ConclusionsThe main reason the trial was stopped related to the high proportion of women ineligible for recruitment due to prior treatment with study drug(s) because of unanticipated changes in clinical practice. The qualitative results also demonstrate the impact of the trial on women and staff and highlight how the diversity of referral pathways, boundaries of care and the complexity of the trial and protocol resulted in additional barriers to successful trial recruitment. Qualitative work in pilot and feasibility studies of a clinical trial is recommended, to evaluate whether recruitment strategies remain viable in unanticipated contexts.Trial registrationTrial registration number ISRCTN16924692 . Date: 08/01/2018.

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IFN-? induces aberrant CD49b? NK cell recruitment through regulating CX3CL1: a novel mechanism by which IFN-? provokes pregnancy failure.

Publications

IFN-γ induces aberrant CD49b⁺ NK cell recruitment through regulating CX3CL1: a novel mechanism by which IFN-γ provokes pregnancy failure.

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