Downregulation of NK cell-mediated swine endothelial cell lysis by DAF (CD55)

Kusama, Tadashi; Miyagawa, Shuji; Moritan, Toshiyuki; Kubo, Takekazu; Yamada, Masashi; Sata, Hiroshi; Fukuta, Daisuke; Matsunami, Katsuyoshi; Shirakura, R

doi:10.1016/s0041-1345(02)03834-4

Cited by 6 publications

(4 citation statements)

References 9 publications

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“…In contrast, no significant effect was noted after downregulation of CD46 by siRNA. Although surprising, these results obtained in the absence of serum as source of complement are in agreement with those of other groups who have previously suggested additional novel functions for CD55 and CD59 in tumour immune surveillance that may be unrelated to complement inhibition (Finberg et al , 1992; Caragine et al , 2002; Kusama et al , 2003; Macor et al , 2007). Indeed, blocking of CD55 and CD59 by antibodies and/or miniantibodies was recently reported to increase not only complement but also PBL-mediated killing of human lymphoma cells triggered by rituximab (Macor et al , 2007).…”

Section: Discussionsupporting

confidence: 91%

Downregulation of membrane complement inhibitors CD55 and CD59 by siRNA sensitises uterine serous carcinoma overexpressing Her2/neu to complement and antibody-dependent cell cytotoxicity in vitro: implications for trastuzumab-based immunotherapy

et al. 2012

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Background:We evaluated the expression of CD46, CD55 and CD59 membrane-bound complement-regulatory proteins (mCRPs) in primary uterine serous carcinoma (USC) and the ability of small interfering RNA (siRNA) against these mCRPs to sensitise USC to complement-dependent cytotoxicity (CDC) and antibody (trastuzumab)-dependent cellular cytotoxicity (ADCC) in vitro.Methods:Membrane-bound complement-regulatory proteins expression was evaluated using real-time PCR (RT–PCR) and flow cytometry, whereas Her2/neu expression and c-erbB2 gene amplification were assessed using immunohistochemistry, flow cytometry and fluorescent in-situ hybridisation. The biological effect of siRNA-mediated knockdown of mCRPs on HER2/neu-overexpressing USC cell lines was evaluated in CDC and ADCC 4-h chromium-release assays.Results:High expression of mCRPs was found in USC cell lines when compared with normal endometrial cells (P<0.05). RT–PCR and FACS analyses demonstrated that anti-mCRP siRNAs were effective in reducing CD46, CD55 and CD59 expression on USC (P<0.05). Baseline complement-dependent cytotoxicity (CDC) against USC cell lines was low (mean±s.e.m.=6.8±0.9%) but significantly increased upon CD55 and CD59 knockdown (11.6±0.8% and 10.7±0.9%, respectively, P<0.05). Importantly, in the absence of complement, both CD55 and CD59, but not CD46, knockdowns significantly augmented ADCC against USC overexpressing Her2/neu.Conclusion:Uterine serous carcinoma express high levels of the mCRPs CD46, CD55 and CD59. Small interfering RNA inhibition of CD55 and CD59, but not CD46, sensitises USC to both CDC and ADCC in vitro, and if specifically targeted to tumour cells, may significantly increase trastuzumab-mediated therapeutic effect in vivo.

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Section: Discussionsupporting

confidence: 91%

Downregulation of membrane complement inhibitors CD55 and CD59 by siRNA sensitises uterine serous carcinoma overexpressing Her2/neu to complement and antibody-dependent cell cytotoxicity in vitro: implications for trastuzumab-based immunotherapy

et al. 2012

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“…We found that DN Treg cells overexpressed CD55 and VEGF, whereas mutant clones did not show significant increases in expression of any survival genes. It has been demonstrated that CD55 prevents cell death through complement activation (57,58), whereas VEGF has been implicated in cell proliferation (59,60). This supports the observation that DN Treg cells are highly resistant to activation induced cell death (55,56).…”

Section: -Fold Higher By Qrt-pcr)mentioning

confidence: 99%

Expression Profiling of Murine Double-Negative Regulatory T Cells Suggest Mechanisms for Prolonged Cardiac Allograft Survival

Lee

Mansfield²,

Hsieh³

et al. 2005

The Journal of Immunology

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Recent studies have demonstrated that both mouse and human αβTCR+CD3+NK1.1−CD4−CD8− double-negative regulatory T (DN Treg) cells can suppress Ag-specific immune responses mediated by CD8+ and CD4+ T cells. To identify molecules involved in DN Treg cell function, we generated a panel of murine DN Treg clones, which specifically kill activated syngeneic CD8+ T cells. Through serial cultivation of DN Treg clones, mutant clones arose that lost regulatory capacity in vitro and in vivo. Although all allogeneic cardiac grafts in animals preinfused with tolerant CD4/CD8 negative 12 DN Treg clones survived over 100 days, allograft survival is unchanged following infusion of mutant clones (19.5 ± 11.1 days) compared with untreated controls (22.8 ± 10.5 days; p < 0.001). Global gene expression differences between functional DN Treg cells and nonfunctional mutants were compared. We found 1099 differentially expressed genes (q < 0.025%), suggesting increased cell proliferation and survival, immune regulation, and chemotaxis, together with decreased expression of genes for Ag presentation, apoptosis, and protein phosphatases involved in signal transduction. Expression of 33 overexpressed and 24 underexpressed genes were confirmed using quantitative real-time PCR. Protein expression of several genes, including FcεRIγ subunit and CXCR5, which are >50-fold higher, was also confirmed using FACS. These findings shed light on the mechanisms by which DN Treg cells down-regulate immune responses and prolong cardiac allograft survival.

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“…Based on the above, it is reasonable to assume that the observed modulation by miR-150, miR-328, and miR-616 of the expression of mitochondrial resilient proteins will also affect CTL and NK cell-mediated cytotoxicity. Two complement membrane regulators, CD55 (71,72) and CD59 (73), inhibit NK-mediated cytotoxicity. As shown here, miR-150 upregulated CD55 expression, and miR-616 downregulated CD59 expression.…”

Section: Discussionmentioning

confidence: 99%

MicroRNAs Affect Complement Regulator Expression and Mitochondrial Activity to Modulate Cell Resistance to Complement-Dependent Cytotoxicity

Hillman

Mardamshina

Pasmanik‐Chor

et al. 2019

Cancer Immunology Research

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MicroRNAs (miR) are small RNA molecules that shape the cell transcriptome and proteome through regulation of mRNA stability and translation. Here, we examined their function as determinants of cell resistance to complement-dependent cytotoxicity (CDC). To achieve this goal, we compared the expression of microRNAs between complement-resistant and -sensitive K562 leukemia, Raji lymphoma, and HCT-116 colorectal carcinoma cells. Global microRNA array analysis identified miR-150, miR-328, and miR-616 as regulators of CDC resistance. Inhibition of miR-150 reduced resistance, whereas inhibition of miR-328 or miR-616 enhanced cell resistance. Treatment of K562 cells with a sublytic dose of complement was shown to rapidly increase miR-150, miR-328, and miR-616 expression. Protein targets of these microRNAs were analyzed in K562 cells by mass spectrometry-based proteomics. Expression of the complement membrane regulatory proteins CD46 and CD59 was significantly enhanced after inhibition of miR-328 and miR-616. Enrichment of proteins of mitochondria, known target organelles in CDC, was observed after miR-150, miR-328, and miR-616 inhibition. In conclusion, miR-150, miR-328, and miR-616 regulate cell resistance to CDC by modifying the expression of the membrane complement regulators CD46 and CD59 and the response of the mitochondria to complement lytic attack. These microRNAs may be considered targets for intervention in complement-associated diseases and in anticancer, complementbased therapy.

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Downregulation of NK cell-mediated swine endothelial cell lysis by DAF (CD55)

Cited by 6 publications

References 9 publications

Downregulation of membrane complement inhibitors CD55 and CD59 by siRNA sensitises uterine serous carcinoma overexpressing Her2/neu to complement and antibody-dependent cell cytotoxicity in vitro: implications for trastuzumab-based immunotherapy

Downregulation of membrane complement inhibitors CD55 and CD59 by siRNA sensitises uterine serous carcinoma overexpressing Her2/neu to complement and antibody-dependent cell cytotoxicity in vitro: implications for trastuzumab-based immunotherapy

Expression Profiling of Murine Double-Negative Regulatory T Cells Suggest Mechanisms for Prolonged Cardiac Allograft Survival

MicroRNAs Affect Complement Regulator Expression and Mitochondrial Activity to Modulate Cell Resistance to Complement-Dependent Cytotoxicity

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