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Split anergized Natural Killer cells halt inflammation by inducing stem cell differentiation, resistance to NK cell cytotoxicity and prevention of cytokine and chemokine secretion.

Tseng HC, Cacalano N, Jewett A - Oncotarget (2015)

Bottom Line: In contrast, inhibition of cytokine and chemokine release was mediated by IFN-γ since the addition of anti-IFN-γ antibody, and not anti-TNF-α, restored secretion of inflammatory mediators in NK cell cultures with differentiated DPSCs and OSCSCs.There was a gradual and time dependent decrease in MHC class I and CD54 expression which correlated with the restoration of NK cell cytotoxicity, augmentation of cytokine secretion and increased cell growth from days 0-12 post NK removal.Continuous presence of NK cells is required for the maintenance of cell differentiation since the removal of NK cell-mediated function reverses the phenotype and function of differentiated cells to their stem-like cells.

View Article: PubMed Central - PubMed

Affiliation: Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Los Angeles, CA, USA.

ABSTRACT
The mechanism of suppression of NK cytotoxicity in cancer patients is not clearly established. In this paper we provide evidence that anergized NK cells induce differentiation of healthy Dental Pulp Stem Cells (DPSCs) or transformed Oral Squamous Cancer Stem Cells (OSCSCs) resulting in cell growth inhibition, resistance to NK cell-mediated cytotoxicity and prevention of inflammatory mediators secretion. Induction of cytotoxicity resistance in differentiated cells correlated with increased CD54 and MHC class I surface expression and mediated by the combination of IFN-γ and TNF-α since antibodies to both, but not each cytokine alone, was able to inhibit resistance. In contrast, inhibition of cytokine and chemokine release was mediated by IFN-γ since the addition of anti-IFN-γ antibody, and not anti-TNF-α, restored secretion of inflammatory mediators in NK cell cultures with differentiated DPSCs and OSCSCs. There was a gradual and time dependent decrease in MHC class I and CD54 expression which correlated with the restoration of NK cell cytotoxicity, augmentation of cytokine secretion and increased cell growth from days 0-12 post NK removal. Continuous presence of NK cells is required for the maintenance of cell differentiation since the removal of NK cell-mediated function reverses the phenotype and function of differentiated cells to their stem-like cells.

No MeSH data available.


Related in: MedlinePlus

Decreased numbers of OSCSCs after treatment with supernatants from IL-2+anti-CD16mAb treated NK cellsOSCSCs were treated with supernatants from IL-2+anti-CD16mAb treated NK cells for 4 days (day 0 of post-differentiation) after which treated OSCSCs were washed and cultured in media for an additional 2, 6 and 12 days. The ratios of tumor growth were determined by comparing the number of IL-2+anti-CD16mAb treated NK supernatant differentiated OSCSCs with untreated OSCSCs at each time point.
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Figure 4: Decreased numbers of OSCSCs after treatment with supernatants from IL-2+anti-CD16mAb treated NK cellsOSCSCs were treated with supernatants from IL-2+anti-CD16mAb treated NK cells for 4 days (day 0 of post-differentiation) after which treated OSCSCs were washed and cultured in media for an additional 2, 6 and 12 days. The ratios of tumor growth were determined by comparing the number of IL-2+anti-CD16mAb treated NK supernatant differentiated OSCSCs with untreated OSCSCs at each time point.

Mentions: To determine growth dynamics of OSCSCs after treatment with the NK supernatants, the numbers of OSCSCs were counted after treatment with the NK cell supernatants by microscopic evaluation and the levels of cell death were determined by staining with propidium iodide followed by flow cytometric analysis. As shown in Figure 4 there was a decrease in the numbers of OSCSCs after their treatment with IL-2+anti-CD16mAb treated NK cell supernatants when compared to untreated OSCSCs or those cultured with untreated NK cell supernatants (Figure 4). In addition, the decrease in the rate of cell growth was completely inhibited in the presence of the combination of anti-IFN-γ and anti-TNF-α antibodies and not each antibody alone [32]. Interestingly, at day 12 of post supernatant removal the rate of growth in OSCSCs treated with supernatants from IL-2+anti-CD16mAb treated NK cells increased 2 fold when compared to OSCSCs cultured either with untreated NK cell supernatants or untreated OSCSCs (Figure 4). Moreover, when the viability of OSCSCs were determined after the addition of supernatants from the IL-2+anti-CD16mAb treated NK cells, no significant cell death in the OSCSCs were seen at day 0 (Supplementary Figure 3) or at days 2–12 after supernatant removal (data not shown).


Split anergized Natural Killer cells halt inflammation by inducing stem cell differentiation, resistance to NK cell cytotoxicity and prevention of cytokine and chemokine secretion.

Tseng HC, Cacalano N, Jewett A - Oncotarget (2015)

Decreased numbers of OSCSCs after treatment with supernatants from IL-2+anti-CD16mAb treated NK cellsOSCSCs were treated with supernatants from IL-2+anti-CD16mAb treated NK cells for 4 days (day 0 of post-differentiation) after which treated OSCSCs were washed and cultured in media for an additional 2, 6 and 12 days. The ratios of tumor growth were determined by comparing the number of IL-2+anti-CD16mAb treated NK supernatant differentiated OSCSCs with untreated OSCSCs at each time point.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496194&req=5

Figure 4: Decreased numbers of OSCSCs after treatment with supernatants from IL-2+anti-CD16mAb treated NK cellsOSCSCs were treated with supernatants from IL-2+anti-CD16mAb treated NK cells for 4 days (day 0 of post-differentiation) after which treated OSCSCs were washed and cultured in media for an additional 2, 6 and 12 days. The ratios of tumor growth were determined by comparing the number of IL-2+anti-CD16mAb treated NK supernatant differentiated OSCSCs with untreated OSCSCs at each time point.
Mentions: To determine growth dynamics of OSCSCs after treatment with the NK supernatants, the numbers of OSCSCs were counted after treatment with the NK cell supernatants by microscopic evaluation and the levels of cell death were determined by staining with propidium iodide followed by flow cytometric analysis. As shown in Figure 4 there was a decrease in the numbers of OSCSCs after their treatment with IL-2+anti-CD16mAb treated NK cell supernatants when compared to untreated OSCSCs or those cultured with untreated NK cell supernatants (Figure 4). In addition, the decrease in the rate of cell growth was completely inhibited in the presence of the combination of anti-IFN-γ and anti-TNF-α antibodies and not each antibody alone [32]. Interestingly, at day 12 of post supernatant removal the rate of growth in OSCSCs treated with supernatants from IL-2+anti-CD16mAb treated NK cells increased 2 fold when compared to OSCSCs cultured either with untreated NK cell supernatants or untreated OSCSCs (Figure 4). Moreover, when the viability of OSCSCs were determined after the addition of supernatants from the IL-2+anti-CD16mAb treated NK cells, no significant cell death in the OSCSCs were seen at day 0 (Supplementary Figure 3) or at days 2–12 after supernatant removal (data not shown).

Bottom Line: In contrast, inhibition of cytokine and chemokine release was mediated by IFN-γ since the addition of anti-IFN-γ antibody, and not anti-TNF-α, restored secretion of inflammatory mediators in NK cell cultures with differentiated DPSCs and OSCSCs.There was a gradual and time dependent decrease in MHC class I and CD54 expression which correlated with the restoration of NK cell cytotoxicity, augmentation of cytokine secretion and increased cell growth from days 0-12 post NK removal.Continuous presence of NK cells is required for the maintenance of cell differentiation since the removal of NK cell-mediated function reverses the phenotype and function of differentiated cells to their stem-like cells.

View Article: PubMed Central - PubMed

Affiliation: Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Los Angeles, CA, USA.

ABSTRACT
The mechanism of suppression of NK cytotoxicity in cancer patients is not clearly established. In this paper we provide evidence that anergized NK cells induce differentiation of healthy Dental Pulp Stem Cells (DPSCs) or transformed Oral Squamous Cancer Stem Cells (OSCSCs) resulting in cell growth inhibition, resistance to NK cell-mediated cytotoxicity and prevention of inflammatory mediators secretion. Induction of cytotoxicity resistance in differentiated cells correlated with increased CD54 and MHC class I surface expression and mediated by the combination of IFN-γ and TNF-α since antibodies to both, but not each cytokine alone, was able to inhibit resistance. In contrast, inhibition of cytokine and chemokine release was mediated by IFN-γ since the addition of anti-IFN-γ antibody, and not anti-TNF-α, restored secretion of inflammatory mediators in NK cell cultures with differentiated DPSCs and OSCSCs. There was a gradual and time dependent decrease in MHC class I and CD54 expression which correlated with the restoration of NK cell cytotoxicity, augmentation of cytokine secretion and increased cell growth from days 0-12 post NK removal. Continuous presence of NK cells is required for the maintenance of cell differentiation since the removal of NK cell-mediated function reverses the phenotype and function of differentiated cells to their stem-like cells.

No MeSH data available.


Related in: MedlinePlus