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  3. Lactic acid inhibits iNKT cell functions via a phosphodiesterase-5 dependent pathway

Lactic acid inhibits iNKT cell functions via a phosphodiesterase-5 dependent pathway

  • Biochem Biophys Res Commun. 2021 Apr 2;547:9-14. doi: 10.1016/j.bbrc.2021.02.012.
Lili Wang 1,  Qielan Wu 1,  Jiwei Liu 1,  Huimin Zhang 2,  Li Bai 3
Affiliations

Affiliations

  • 1 Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, China.
  • 2 Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, China. Electronic address: [email protected].
  • 3 Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, China. Electronic address: [email protected].
PMID: 33588236 DOI: 10.1016/j.bbrc.2021.02.012
Abstract

Lactic acid in tumor microenvironment inhibits iNKT cell functions and thus dampens their anti-tumor efficacy. The underlying mechanisms remain unclear. Here, we show that phosphodiesterase-5 inhibitors, sildenafil and tadalafil, promote IFN-γ and IL-4 production in iNKT cells in a cGMP-PKG pathway dependent manner. To favor their cytokine production, iNKT cells reduce Pde5a mRNA lever after activation. In line with the reduction of cytokines caused by lactic acid, lactic acid elevates Pde5a mRNA lever in activated iNKT cells. As a result, phosphodiesterase-5 inhibitor partially restores the cytokine production in lactic acid-treated cells. Our results demonstrate that phosphodiesterase-5 inhibits cytokine production in iNKT cells, and that contributes to the lactic acid-caused dysfunction of iNKT cells.

Keywords

IFN-γ; IL-4; PDE5; cGMP-PKG; iNKT cells.

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