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Article Open Access

MFG-E8 inhibits neutrophil migration through αvβ3-integrin-dependent MAP kinase activation

  • Authors:
    • Monowar Aziz
    • Weng‑Lang Yang
    • Lana M. Corbo
    • Wayne W. Chaung
    • Shingo Matsuo
    • Ping Wang
  • View Affiliations / Copyright

    Affiliations: Center for Translational Research, The Feinstein Institute for Medical Research and Department of Surgery, Hofstra North Shore‑LIJ School of Medicine, Manhasset, NY, USA
    Copyright: © Aziz et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].
  • Pages: 18-28
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    Published online on: April 23, 2015
       https://doi.org/10.3892/ijmm.2015.2196
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Abstract

We have previously demonstrated the involvement of milk fat globule-epidermal growth factor-factor 8 (MFG‑E8) in reducing neutrophil infiltration in a murine model of acute lung injury (ALI). In the present study, we aimed to delineate the mechanisms through which MFG‑E8 attenuates neutrophil migration. Recombinant human MFG‑E8 (rhMFG‑E8) was expressed and purified in our facility. The human differentiated neutrophil cell line, dHL‑60, was treated with rhMFG‑E8 and cell migration assay was performed in a Boyden chamber using recombinant interleukin‑8 (IL‑8) as the chemoattractant. Surface CXCR2 and intracellular G protein‑coupled receptor kinase 2 (GRK2) levels were evaluated by flow cytometry or western blot analysis. The levels of mitogen‑activated protein (MAP) kinases were determined by western blot analysis. Treatment with rhMFG‑E8 resulted in a significant inhibition of dHL‑60 cell migration in a dose‑dependent manner. There was a 46% decrease in CXCR2 expression in the rhMFG‑E8‑treated dHL‑60 cells, which was associated with a 32% increase in GRK2 expression. In the dHL‑60 cells, treatment with rhMFG‑E8 promoted the phosphorylation of p38 and extracellular signal-regulated kinase (ERK) within 10‑30 min. The use of SB203580, a p38 inhibitor, and PD98059, an ERK inhibitor, resulted in the restoration of dHL‑60 cell migration which was significantly inhibited treatment with rhMFG‑E8. Furthermore, blocking the MFG‑E8 receptors, αvβ3/αvβ5‑integrins, by anti‑αv‑integrin neutralizing antibody (Ab) inhibited the activation of p38 and ERK, and reversed the rhMFG‑E8‑induced inhibition of dHL‑60 cell migration. Finally, treatment of the dHL‑60 cells with SB203580 and PD98059 neutralized the rhMFG‑E8‑induced downregulation of CXCR2 expression and upregulation of GRK2 expression, as well as the inhibitory effects on cell migration. Our findings reveal a novel mechanism of action of MFG‑E8 through which it inhibits neutrophil migration through αvβ3-integrin-dependent MAP kinase activation.
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Copy and paste a formatted citation
Spandidos Publications style
Aziz M, Yang WL, Corbo LM, Chaung WW, Matsuo S and Wang P: MFG-E8 inhibits neutrophil migration through αvβ3-integrin-dependent MAP kinase activation. Int J Mol Med 36: 18-28, 2015.
APA
Aziz, M., Yang, W., Corbo, L.M., Chaung, W.W., Matsuo, S., & Wang, P. (2015). MFG-E8 inhibits neutrophil migration through αvβ3-integrin-dependent MAP kinase activation. International Journal of Molecular Medicine, 36, 18-28. https://doi.org/10.3892/ijmm.2015.2196
MLA
Aziz, M., Yang, W., Corbo, L. M., Chaung, W. W., Matsuo, S., Wang, P."MFG-E8 inhibits neutrophil migration through αvβ3-integrin-dependent MAP kinase activation". International Journal of Molecular Medicine 36.1 (2015): 18-28.
Chicago
Aziz, M., Yang, W., Corbo, L. M., Chaung, W. W., Matsuo, S., Wang, P."MFG-E8 inhibits neutrophil migration through αvβ3-integrin-dependent MAP kinase activation". International Journal of Molecular Medicine 36, no. 1 (2015): 18-28. https://doi.org/10.3892/ijmm.2015.2196
Copy and paste a formatted citation
x
Spandidos Publications style
Aziz M, Yang WL, Corbo LM, Chaung WW, Matsuo S and Wang P: MFG-E8 inhibits neutrophil migration through αvβ3-integrin-dependent MAP kinase activation. Int J Mol Med 36: 18-28, 2015.
APA
Aziz, M., Yang, W., Corbo, L.M., Chaung, W.W., Matsuo, S., & Wang, P. (2015). MFG-E8 inhibits neutrophil migration through αvβ3-integrin-dependent MAP kinase activation. International Journal of Molecular Medicine, 36, 18-28. https://doi.org/10.3892/ijmm.2015.2196
MLA
Aziz, M., Yang, W., Corbo, L. M., Chaung, W. W., Matsuo, S., Wang, P."MFG-E8 inhibits neutrophil migration through αvβ3-integrin-dependent MAP kinase activation". International Journal of Molecular Medicine 36.1 (2015): 18-28.
Chicago
Aziz, M., Yang, W., Corbo, L. M., Chaung, W. W., Matsuo, S., Wang, P."MFG-E8 inhibits neutrophil migration through αvβ3-integrin-dependent MAP kinase activation". International Journal of Molecular Medicine 36, no. 1 (2015): 18-28. https://doi.org/10.3892/ijmm.2015.2196
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