Role of <scp>NK</scp>p46 Expression in Cytokine Production by <scp>CD</scp>56‐Positive <scp>NK</scp> Cells in the Peripheral Blood and the Uterine Endometrium

Yokota, Megumi; Fukui, Atsushi; Funamizu, Ayano; Nakamura, Rika; Kamoi, Mai; Fuchinoue, Kohei; Sasaki, Yukie; Fukuhara, Rie; Mizunuma, Hideki

doi:10.1111/aji.12062

Cited by 30 publications

(22 citation statements)

References 33 publications

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“…Similarly, Zhang et al 25 reported higher expression of NKp46 on decidual NK cells from patients undergoing spontaneous abortions. Engagement of NKp46 on decidual NK cells was observed by Hicham et al 26 to increase cytotoxicity of decidual NK cells, and Yokota et al 27 recently reported that NKp46 regulates cytokine production by endometrial NK cells. Thus, simlar to CD16, the association between NKp46 and reproductive failure may relate to the increased cytotoxic activity and dysregulation of cytokine production following engagement of NKp46 on uterine NK cells.…”

Section: Discussionmentioning

confidence: 89%

Characterization of Uterine NK Cells in Women with Infertility or Recurrent Pregnancy Loss and Associated Endometriosis

Giuliani

Parkin

Lessey

et al. 2014

American J Rep Immunol

142

106

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Problem Uterine natural killer cells (uNK) have been thought to play a key role in endometriosis and infertility. We investigated the expression of CD56, CD16 and NKp46 in endometrial tissues from 61 women with unexplained recurrent pregnancy loss (uRPL) or infertility (UI), and correlated this with the presence or absence of endometriosis. The results from the patients with sub-fertility were compared to those from 10 fertile patients. Method of study Mid-secretory phase endometrial biopsies were obtained and the endometrial expression of CD56, CD16 or NKp46 was identified by immunohistochemistry and quantified (ImageJ Software). Results The percentage of CD16+ cells was higher in women with uRPL (7.9±3.2) and UI (9.0±5.5), even when these conditions were associated with endometriosis (8.9±5.3), compared to fertile patients (5.6±2.4, p<0.05). Likewise, the ratio of NKp46+:CD56+ cells was higher in women with uRPL (0.28±0.25) and UI (0.21±0.2), even when these conditions were associated with endometriosis (0.19±0.14), compared to fertile patients (0.1±0.1, p<0.05). No differences were observed when comparing CD56. Conclusions Women, with or without endometriosis, who have larger populations of cytotoxic CD16+ uNK cells and/or higher populations of NKp46+CD56+ cells may be at greater risk for infertility disorders resulting from an inflammtory environment occuring during implantation or later during decidualization.

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Section: Discussionmentioning

confidence: 89%

Characterization of Uterine NK Cells in Women with Infertility or Recurrent Pregnancy Loss and Associated Endometriosis

Giuliani

Parkin

Lessey

et al. 2014

American J Rep Immunol

142

106

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“…NKp30 and NKp46 perform functions in the cytotoxic activity and cytokine production of NK cells. Recently, we have shown a functional role for NKp46 in cytokine production by NK cells in an in vitro study on the peripheral blood and uterine endometrium of women with reproductive failure, such as RPL . Interestingly, the expression of NKp46 was associated with cytokine‐production in both CD56 bright and CD56 dim NK cells.…”

Section: Discussionmentioning

confidence: 95%

“…Recently, we have shown a functional role for NKp46 in cytokine production by NK cells in an in vitro study on the peripheral blood and uterine endometrium of women with reproductive failure, such as RPL. 24 Interestingly, the expression of NKp46 was associated with cytokine-production in both CD56 bright and CD56 dim NK cells. Moreover, the intensity of NKp46 was associated with cytokine production by NK cells, especially IFN-γ production.…”

Section: Discussionmentioning

confidence: 97%

“…That is, NKp46 bright NK cells produced more cytokines than NKp46 dim NK cells. Besides, among the NK cell subtypes, CD56 bright /NKp46 bright NK cells produce the most IFN‐γ . A previous study examined the relation between the expression of NCR and cytokines production for decidual NK cells, reporting that NKp46 + decidual NK cells did not have function for cytokine secretion, but that NKp44 + and NKp30 + decidual NK cells did.…”

Section: Discussionmentioning

confidence: 99%

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Expression of natural cytotoxicity receptors and cytokine production on endometrial natural killer cells in women with recurrent pregnancy loss or implantation failure, and the expression of natural cytotoxicity receptors on peripheral blood natural killer cells in pregnant women with a history of recurrent pregnancy loss

Fukui

Funamizu

Fukuhara

et al. 2017

J of Obstet and Gynaecol

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Aim: Natural cytotoxicity receptors (NCR) are unique markers that regulate natural killer (NK) cell cytotoxicity and cytokine production. In this study, we investigated the expression of NCR (NKp46, NKp44, and NKp30) and cytokine production in NK cells derived from the uterine endometrium of women with recurrent pregnancy loss (RPL). We also investigated the expression of NCR in peripheral blood NK cells in pregnant women with and without a history of RPL. Methods: The expression of NCR (NKp46, NKp44, and NKp30) in NK cells (CD56 dim and CD56 bright ) in the uterine endometrium was analyzed using 3-color flow cytometry. Cytokine (tumor necrosis factor-α and interferon-γ) production was also analyzed. NK cells from the mid-secretory endometrium of 28 women with RPL, 34 women with implantation failure, and 74 controls were collected and mechanically dispersed using a tissue grinder. The expression of NCR in peripheral blood NK cells from pregnant women with (n = 17) and without (n = 91) a history of RPL was analyzed. Results: The percentages of NKp46 + NK cells were significantly lower in both women with RPL and pregnant women with a history of RPL. The percentages of tumor necrosis factor-α-and/or interferon-γ-producing uterine endometrial NK cells were significantly lower in women with RPL compared with controls. Conclusion: The changes in NCR expression and cytokine production, especially decreased NKp46 expression in endometrial NK cells, suggests the presence of abnormal NK cell regulation in women with reproductive failures.

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“…More interestingly, a high number of NK cells in the uterine endometrium expressing almost exclusively CD56 bright and producing IL-4 and IL-10 have been shown to play an important role in trophoblast invasion, development of placenta, angiogenesis, and maintenance of the early pregnancy 51, 52, 53, 54. Immunoregulatory CD56 bright cells, able to downregulate the immune responses and reduce inflammation by producing the immunosuppressive cytokine IL-10, were observed also in context of different diseases 52 .…”

Section: Discussionmentioning

confidence: 99%

Humanized Mice with Subcutaneous Human Solid Tumors for Immune Response Analysis of Vaccinia Virus-Mediated Oncolysis

Tsoneva

Minev

Frentzen

et al. 2017

Molecular Therapy - Oncolytics

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Oncolytic vaccinia virus (VACV) therapy is an alternative cancer treatment modality that mediates targeted tumor destruction through a tumor-selective replication and an induction of anti-tumor immunity. We developed a humanized tumor mouse model with subcutaneous human tumors to analyze the interactions of VACV with the developing tumors and human immune system. A successful systemic reconstitution with human immune cells including functional T cells as well as development of tumors infiltrated with human T and natural killer (NK) cells was observed. We also demonstrated successful in vivo colonization of such tumors with systemically administered VACVs. Further, a new recombinant GLV-1h376 VACV encoding for a secreted human CTLA4-blocking single-chain antibody (CTLA4 scAb) was tested. Surprisingly, although proving CTLA4 scAb’s in vitro binding ability and functionality in cell culture, beside the significant increase of CD56bright NK cell subset, GLV-1h376 was not able to increase cytotoxic T or overall NK cell levels at the tumor site. Importantly, the virus-encoded β-glucuronidase as a measure of viral titer and CTLA4 scAb amount was demonstrated. Therefore, studies in our “patient-like” humanized tumor mouse model allow the exploration of newly designed therapy strategies considering the complex relationships between the developing tumor, the oncolytic virus, and the human immune system.

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Role of NKp46 Expression in Cytokine Production by CD56‐Positive NK Cells in the Peripheral Blood and the Uterine Endometrium

Abstract: Expression of NKp46 is involved in cytokine production of CD56(+) NK cells in the peripheral blood and the uterine endometrium.

Cited by 30 publications

References 33 publications

Characterization of Uterine NK Cells in Women with Infertility or Recurrent Pregnancy Loss and Associated Endometriosis

Characterization of Uterine NK Cells in Women with Infertility or Recurrent Pregnancy Loss and Associated Endometriosis

Humanized Mice with Subcutaneous Human Solid Tumors for Immune Response Analysis of Vaccinia Virus-Mediated Oncolysis

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