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Research ArticleInflammation, Immunopharmacology, and Asthma

RhoA/Phosphatidylinositol 3-Kinase/Protein Kinase B/Mitogen-Activated Protein Kinase Signaling after Growth Arrest–Specific Protein 6/Mer Receptor Tyrosine Kinase Engagement Promotes Epithelial Cell Growth and Wound Repair via Upregulation of Hepatocyte Growth Factor in Macrophages

Ye-Ji Lee, Hyun-Jung Park, So-Youn Woo, Eun-Mi Park and Jihee Lee Kang
Journal of Pharmacology and Experimental Therapeutics September 2014, 350 (3) 563-577; DOI: https://doi.org/10.1124/jpet.114.215673
Ye-Ji Lee
Department of Physiology (Y.-J.L., H.-J.P, S.-Y.W., J.L.K.), Department of Pharmacology (E.-M.P.), Department of Microbiology A (S.-Y.W.), and Tissue Injury Defense Research Center (H.-J.P., S.-Y.W., E.-M.P., J.L.K.), Global Top5 Research Program (J.L.K.), School of Medicine, Ewha Womans University, Seoul, Korea
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Hyun-Jung Park
Department of Physiology (Y.-J.L., H.-J.P, S.-Y.W., J.L.K.), Department of Pharmacology (E.-M.P.), Department of Microbiology A (S.-Y.W.), and Tissue Injury Defense Research Center (H.-J.P., S.-Y.W., E.-M.P., J.L.K.), Global Top5 Research Program (J.L.K.), School of Medicine, Ewha Womans University, Seoul, Korea
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So-Youn Woo
Department of Physiology (Y.-J.L., H.-J.P, S.-Y.W., J.L.K.), Department of Pharmacology (E.-M.P.), Department of Microbiology A (S.-Y.W.), and Tissue Injury Defense Research Center (H.-J.P., S.-Y.W., E.-M.P., J.L.K.), Global Top5 Research Program (J.L.K.), School of Medicine, Ewha Womans University, Seoul, Korea
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Eun-Mi Park
Department of Physiology (Y.-J.L., H.-J.P, S.-Y.W., J.L.K.), Department of Pharmacology (E.-M.P.), Department of Microbiology A (S.-Y.W.), and Tissue Injury Defense Research Center (H.-J.P., S.-Y.W., E.-M.P., J.L.K.), Global Top5 Research Program (J.L.K.), School of Medicine, Ewha Womans University, Seoul, Korea
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Jihee Lee Kang
Department of Physiology (Y.-J.L., H.-J.P, S.-Y.W., J.L.K.), Department of Pharmacology (E.-M.P.), Department of Microbiology A (S.-Y.W.), and Tissue Injury Defense Research Center (H.-J.P., S.-Y.W., E.-M.P., J.L.K.), Global Top5 Research Program (J.L.K.), School of Medicine, Ewha Womans University, Seoul, Korea
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Abstract

Growth arrest–specific protein 6 (Gas6)/Mer receptor tyrosine kinase (Mer) signaling modulates cytokine secretion and helps to regulate the immune response and apoptotic cell clearance. Signaling pathways that activate an epithelial growth program in macrophages are still poorly defined. We report that Gas6/Mer/RhoA signaling can induce the production of epithelial growth factor hepatic growth factor (HGF) in macrophages, which ultimately promotes epithelial cell proliferation and wound repair. The RhoA/protein kinase B (Akt)/mitogen-activated protein (MAP) kinases, including p38 MAP kinase, extracellular signal-regulated protein kinase, and Jun NH2-terminal kinase axis in RAW 264.7 cells, was identified as Gas6/Mer downstream signaling pathway for the upregulation of HGF mRNA and protein. Conditioned medium from RAW 264.7 cells that had been exposed to Gas6 or apoptotic cells enhanced epithelial cell proliferation of the epithelial cell line LA-4 and wound closure. Cotreatment with an HGF receptor-blocking antibody or c-Met antagonist downregulated this enhancement. Inhibition of Mer with small interfering RNA (siRNA) or the RhoA/Rho kinase pathway by RhoA siRNA or Rho kinase pharmacologic inhibitor suppressed Gas6-induced HGF mRNA and protein expression in macrophages and blocked epithelial cell proliferation and wound closure induced by the conditioned medium. Our data provide evidence that macrophages can be reprogrammed by Gas6 to promote epithelial proliferation and wound repair via HGF, which is induced by the Mer/RhoA/Akt/MAP kinase pathway. Thus, defects in Gas6/Mer/RhoA signaling in macrophages may delay tissue repair after injury to the alveolar epithelium.

Footnotes

    • Received April 18, 2014.
    • Accepted June 16, 2014.
  • Y.-J.L. and H.-J.P. contributed equally to this work.

  • This work was supported by a grant from the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea [Grant A121065]; and by a National Research Foundation Grant funded by the Korean government (MSIP) [Grant 2010-0029353].

  • dx.doi.org/10.1124/jpet.114.215673.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 350 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 350, Issue 3
1 Sep 2014
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RhoA/Phosphatidylinositol 3-Kinase/Protein Kinase B/Mitogen-Activated Protein Kinase Signaling after Growth Arrest–Specific Protein 6/Mer Receptor Tyrosine Kinase Engagement Promotes Epithelial Cell Growth and Wound Repair via Upregulation of Hepatocyte …
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Research ArticleInflammation, Immunopharmacology, and Asthma

Gas6/Mer/RhoA in Macrophages Promotes Epithelial Cell Growth

Ye-Ji Lee, Hyun-Jung Park, So-Youn Woo, Eun-Mi Park and Jihee Lee Kang
Journal of Pharmacology and Experimental Therapeutics September 1, 2014, 350 (3) 563-577; DOI: https://doi.org/10.1124/jpet.114.215673

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Research ArticleInflammation, Immunopharmacology, and Asthma

Gas6/Mer/RhoA in Macrophages Promotes Epithelial Cell Growth

Ye-Ji Lee, Hyun-Jung Park, So-Youn Woo, Eun-Mi Park and Jihee Lee Kang
Journal of Pharmacology and Experimental Therapeutics September 1, 2014, 350 (3) 563-577; DOI: https://doi.org/10.1124/jpet.114.215673
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