Larixol inhibits fMLP-induced superoxide anion production and chemotaxis by targeting the βγ subunit of Gi-protein of fMLP receptor in human neutrophils

Hsiang Ruei Liao*, Yu Yao Kao, Yann Lii Leu, Fu Chao Liu, Ching Ping Tseng

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

5 Scopus citations

Abstract

The over-activated neutrophils through G-protein-coupled receptors (GPCRs) caused inflammation or tissue damage. Therefore, GPCRs or their downstream molecules are major targets for inhibiting uncontrolled neutrophil activation. Our studies investigate the action and underlying mechanism of larixol, a diterpene extract from the root of euphorbia formosana, on fMLP-induced neutrophil respiratory burst, chemotaxis, and granular release. The immunoprecipitation assay was performed to investigate whether larixol inhibits fMLP-induced respiratory burst by interfering with the interaction of fMLP receptor Gi-protein βγ subunits with its downstream molecules. Briefly, larixol inhibited fMLP (0.1 μM)-induced superoxide anion production (IC50:1.98 ± 0.14 μM), the release of cathepsin G (IC50:2.76 ± 0.15 μM) and chemotaxis in a concentration-dependent manner; however, larixol did not inhibit these functions induced by PMA (100 nM). Larixol inhibited fMLP-induced Src kinase phosphorylation. Therefore, larixol attenuated the downstream signaling of Src kinases, ERK1/2, p38, and AKT phosphorylation. Moreover, larixol inhibited fMLP-induced intracellular calcium mobilization, PKC phosphorylation, and p47phox translocation from the cytosol to the plasma membrane. Larixol inhibited the interaction of the βγ subunits of Gi-protein of fMLP receptor with Src kinase or with PLCβ by the immunoprecipitation and duolink assay. Furthermore, larixol did not antagonize the formyl peptide receptors. Larixol did not increase cyclic nucleotide levels in neutrophils. These results suggest that larixol modulated fMLP-induced neutrophils superoxide anion production, chemotaxis, and granular releases by interrupting the interaction of the βγ subunits of Gi-protein with downstream signaling of the fMLP receptor.

Original languageEnglish
Article number115091
JournalBiochemical Pharmacology
Volume201
DOIs
StatePublished - 07 2022

Bibliographical note

Publisher Copyright:
© 2022 Elsevier Inc.

Keywords

  • Euphorbia formosana
  • Gi-protein
  • Larixol
  • Neutrophil
  • fMLP

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