Decrease in phosphorylation of ERK following decreased expression of NK cell-activating receptors in human NK cell line exposed to asbestos

Our plain-English summary of Decrease in phosphorylation of ERK following decreased expression of NK cell-activating receptors in human NK cell line exposed to asbestos, by Y. Nishimura, M. Maeda, N. Kumagai, et al (International Journal of Immunopathology and Pharmacology, 2009).

The study

• Authors: Y. Nishimura, M. Maeda, N. Kumagai, H. Hayashi, Y. Miura, T. Otsuki
• Journal: International Journal of Immunopathology and Pharmacology
• Published: 2009;22(4):879-88
• Cited by: 34 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

YT-CB5, which had been continuously cultured with chrysotile B (CB)asbestos, showed impaired cytotoxicity with decreased expression of NKG2D and 2B4 NK cell-activating receptors. In the present study, the phosphorylation of extracellular signal-regulated kinase (ERK), which is known to induce degranulation downstream of many NK cell-activating receptors, was examined in YT-CB5 by flow cytometry and compared with the control line YT-Org. YT-CB5 exhibited impaired phosphorylation of ERK1/2 induced by the recognition of K562 cells, downstream of a process mediated by Src family kinase and phosphoinositide 3-kinase. YT-CB5 also exhibited impaired phosphorylation of ERK1/2 following incubation with K562 cells in the presence of anti-2B4 antibodies, where co-stimulation by 2B4 augmented the phosphorylation of ERK1/2 in YT-CB5 to a similar degree as in YT-Org. The phosphorylation of ERK1/2 induced by an inhibitor against phosphatase (PP) 1 and PP2A was also lower in YT-CB5 compared with YT-Org. Moreover, bead-bound antibodies to NKG2D, which contribute to cytotoxicity against K562 cells, induced negligible phosphorylation of ERK1/2 in YT-CB5, although antibodies to 2B4 induced a comparatively greater level of phosphorylation. Additionally, peripheral blood (PB-) NK cells with low expression of NKG2D showed lower phosphorylation of ERK1/2 mediated by anti-NKG2D antibodies compared with PB-NK cells with high expression of NKG2D. These results indicate that signal transduction events leading to the phosphorylation of ERK is impaired in YT-CB5 due to decreased expression of NKG2D. Further studies are required to clarify whether this suppressive effect of asbestos exposure on NK cells might promote lung cancer and mesothelioma in people who have inhaled asbestos.

In plain English

This was a laboratory (in vitro) study of a human natural killer (NK) cell line. The line YT-A1 had been cultured with chrysotile B asbestos at 0 or 5 micrograms per millilitre for more than five months, giving the control subline YT-Org and the asbestos-exposed subline YT-CB5. Using flow cytometry, the authors measured phosphorylation of ERK1/2, a molecule acting downstream of NK cell-activating receptors. YT-CB5 showed impaired cytotoxicity and decreased cell-surface NKG2D and 2B4, and showed markedly lower phospho-ERK1/2 after incubation with K562 target cells, with a significant difference from YT-Org at 30 minutes. The inhibitors PP2 and wortmannin blocked the increase, indicating Src-family kinase and PI3K involvement. Bead-bound anti-NKG2D antibodies induced only slight phosphorylation in YT-CB5, while anti-2B4 antibodies induced high levels in both sublines. In peripheral blood NK cells from eight healthy volunteers, phosphorylation via NKG2D fell as NKG2D expression fell, with two exceptions. The authors concluded that continuous asbestos exposure can alter activating-receptor expression and so impair NK cytotoxicity.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: In vitro cell-culture experiment using an asbestos-exposed human NK cell line and its control, with additional assays on peripheral blood NK cells from healthy volunteers
• Who was studied: Sublines YT-Org and YT-CB5 of the human NK cell line YT-A1, K562 target cells, and purified peripheral blood NK cells from eight healthy volunteers (Kawasaki Medical School, Japan)
• Exposure: Continuous culture with chrysotile B (CB) asbestos at 5 micrograms per millilitre for more than 5 months (YT-CB5), compared with 0 micrograms per millilitre (YT-Org)
• Main results:
  • YT-CB5 showed impaired cytotoxicity against K562 cells and decreased cell-surface NKG2D and 2B4 compared with YT-Org
  • After incubation with K562 cells, YT-CB5 had markedly lower phospho-ERK1/2 than YT-Org, significantly different at 30 minutes
  • The ERK phosphorylation induced by K562 recognition in YT-Org was blocked by the Src-family kinase inhibitor PP2 and the PI3K inhibitor wortmannin; the low level in YT-CB5 was likewise reduced to background
  • Co-stimulation with anti-2B4 antibodies significantly increased phospho-ERK1/2 in both lines, but YT-CB5 stayed significantly lower than YT-Org
  • With the PP1/PP2A inhibitor calyculin A at 50 nM, YT-CB5 showed significantly less phospho-ERK1/2 than YT-Org
  • At 100 nM calyculin A, ERK phosphorylation in YT-CB5 reached the same level as in YT-Org
  • Bead-bound anti-NKG2D antibodies induced only slight ERK1/2 phosphorylation in YT-CB5, whereas bead-bound anti-2B4 antibodies induced high levels in both lines, higher in YT-CB5
  • In peripheral blood NK cells, ERK1/2 phosphorylation via NKG2D decreased as NKG2D surface expression decreased, although two individuals showed markedly high phosphorylation; phosphorylation via 2B4 stayed high even at the lowest 2B4 expression
• The authors' conclusion: The authors concluded that continuous asbestos exposure can alter expression of NK cell-activating receptors, leading to impaired NK cytotoxicity mediated by decreased ERK phosphorylation, and that this might contribute to tumour development in people who have inhaled asbestos, though further study is needed
• Limitations the authors state:
  • Two volunteers' NK cells did not fit the pattern, so factors other than NKG2D expression may affect ERK phosphorylation
  • The possible phosphorylation/dephosphorylation imbalance in YT-CB5 may be limited, since 100 nM calyculin A restored phosphorylation to control levels
  • Whether this suppressive effect promotes lung cancer and mesothelioma in exposed people remains to be clarified

Topics

The National Library of Medicine indexes this study under subjects our site covers: Chrysotile.

Medical terms in this study, explained in our Lexicon: Chrysotile, Asbestos Exposure, Lung Cancer, Mesothelioma.

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