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Research ArticleInflammation, Immunopharmacology, and Asthma

Fingolimod Phosphate (FTY720-P) Activates Protein Phosphatase 2A in Human Monocytes and Inhibits Monosodium Urate Crystal–Induced Interleukin-1β Production

Marwa Qadri, Sandy ElSayed and Khaled A. Elsaid
Journal of Pharmacology and Experimental Therapeutics February 2021, 376 (2) 222-230; DOI: https://doi.org/10.1124/jpet.120.000321
Marwa Qadri
Department of Pharmacology, College of Pharmacy, Jazan University, Jazan, Kingdom of Saudi Arabia (M.Q.) and Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Rinker Health Sciences Campus, Irvine, California (S.E., K.A.E.)
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Sandy ElSayed
Department of Pharmacology, College of Pharmacy, Jazan University, Jazan, Kingdom of Saudi Arabia (M.Q.) and Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Rinker Health Sciences Campus, Irvine, California (S.E., K.A.E.)
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Khaled A. Elsaid
Department of Pharmacology, College of Pharmacy, Jazan University, Jazan, Kingdom of Saudi Arabia (M.Q.) and Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Rinker Health Sciences Campus, Irvine, California (S.E., K.A.E.)
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Abstract

Gout is a chronic inflammatory arthritis caused by monosodium urate monohydrate (MSU) crystal deposits in joints of lower limbs. Phagocytic uptake of MSU crystals by joint-resident macrophages and recruited circulating monocytes results in IL-1β expression and production. Current acute gout treatments have serious toxicities and suffer suboptimal clinical outcomes. Protein phosphatase 2A (PP2A) plays an important role in regulating signaling pathways relevant to inflammation. We hypothesized that innate immune danger signals, e.g., lipopolysaccharide (LPS) and soluble uric acid (sUA), prime human monocytes toward MSU crystal phagocytosis and that increased IL-1β production mediated by a reduction in PP2A activity and restoring PP2A activity exerts an anti-inflammatory effect in this setting. Priming monocytes with LPS + sUA increased cytosolic pro-IL-1β and mature IL-1β and enhanced MSU crystal phagocytosis and its downstream IL-1β expression (P < 0.001). A combination of LPS + sUA priming and MSU crystals reduced PP2A activity in monocytes by 60% (P = 0.013). PP2A catalytic subunit gene knockdown reduced PP2A activity and exacerbated MSU crystal–induced IL-1β expression and secretion (P < 0.0001). Fingolimod (FTY720) and its active metabolite, fingolimod phosphate (FTY720-P), were evaluated for their ability to activate PP2A in human monocytes over 24 hours. FTY720 and FTY720-P activated PP2A to a similar extent, and maximal enzyme activity occurred at 24 hours for FTY720 and at 6 hours for FTY720-P. FTY720-P (2.5 μM) reduced pro-IL-1β production and IL-1β secretion in primed and MSU crystal–stimulated monocytes (P < 0.0001) without changing the magnitude of crystal phagocytosis. We conclude that PP2A is a promising new target in acute gout.

SIGNIFICANCE STATEMENT The activity of protein phosphatase 2A (PP2A) is implicated in the enhanced expression and production of IL-1β by human monocytes in response to priming with soluble uric acid and lipopolysaccharide and phagocytosis of monosodium urate monohydrate (MSU) crystals. Fingolimod phosphate activates PP2A in human monocytes and reduces cytosolic pro-IL-1β content and its conversion to biologically active IL-1β in human monocytes exposed to MSU crystals.

Footnotes

    • Received September 2, 2020.
    • Accepted November 20, 2020.
  • ↵1 M.Q. and S.E. contributed equally to this work.

  • This work was supported by National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases [Grant R01AR067748].

  • No author has an actual or perceived conflict of interest with the contents of this article.

  • https://doi.org/10.1124/jpet.120.000321.

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 376 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 2
1 Feb 2021
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Research ArticleInflammation, Immunopharmacology, and Asthma

PP2A Is a Novel Therapeutic Target in Gout.

Marwa Qadri, Sandy ElSayed and Khaled A. Elsaid
Journal of Pharmacology and Experimental Therapeutics February 1, 2021, 376 (2) 222-230; DOI: https://doi.org/10.1124/jpet.120.000321

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Research ArticleInflammation, Immunopharmacology, and Asthma

PP2A Is a Novel Therapeutic Target in Gout.

Marwa Qadri, Sandy ElSayed and Khaled A. Elsaid
Journal of Pharmacology and Experimental Therapeutics February 1, 2021, 376 (2) 222-230; DOI: https://doi.org/10.1124/jpet.120.000321
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