Adenosine signaling inhibits CIITA-mediated MHC class II transactivation in lung fibroblast cells

Authors

  • Mingming Fang,

    1. Department of Surgery, Jiangsu Jiankang Vocational College, Nanjing, China
    2. Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
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    • These authors contributed equally to this work.

  • Jun Xia,

    1. Department of Respiratory Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, China
    2. Department of Respiratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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    • These authors contributed equally to this work.

  • Xiaoyan Wu,

    1. Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
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  • Hui Kong,

    1. Department of Respiratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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  • Hong Wang,

    Corresponding author
    • Department of Respiratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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  • Weiping Xie,

    Corresponding author
    • Department of Respiratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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  • Yong Xu

    Corresponding author
    • Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
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Full correspondence:Dr. Yong Xu, Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, Jiangsu, China 210029

Fax: +8625-86862888

e-mail: yxu2005@gmail.com

Additional correspondence: Dr. Hong Wang, Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China

Fax: +8625-83718836

e-mail: hwangnjmu@gmail.com

Additional correspondence: Dr. Weiping Xie, Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China 210029

e-mail: wpxienjmu@gmail.com

Abstract

Efficient antigen presentation by major histocompatibility complex (MHC) molecules represents a critical process in adaptive immunity. Class II transactivator (CIITA) is considered the master regulator of MHC class II (MHC II) transcription. Previously, we have shown that CIITA expression is upregulated in smooth muscle cells deficient in A2b adenosine receptor. Here, we report that treatment with the adenosine receptor agonist adenosine-5′N-ethylcarboxamide (NECA) attenuated MHC II transcription in lung fibro-blast cells as a result of CIITA repression. Further analysis revealed that NECA preferentially abrogated CIITA transcription through promoters III and IV. Blockade with a selective A2b receptor antagonist MRS-1754 restored CIITA-dependent MHC II transactivation. Forskolin, an adenylyl cyclase activator, achieved the same effect as NECA. A2b signaling repressed CIITA transcription by altering histone modifications and recruitment of key factors on the CIITA promoters in a STAT1-dependent manner. MRS-1754 blocked the antagonism of transforming growth factor beta (TGF-β) in CIITA induction by interferon gamma (IFN-γ), alluding to a potential dialogue between TGF-β and adenosine signaling pathways. Finally, A2b signaling attenuated STAT1 phosphorylation and stimulated TGF-β synthesis. In conclusion, we have identified an adenosine-A2b receptor-adenylyl cyclase axis that influences CIITA-mediated MHC II transactivation in lung fibroblast cells and as such have provided invaluable insights into the development of novel immune-modulatory strategies.

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