Abstract
Formyl peptide receptor 1 (FPR1) mediates bacterial and mitochondrial N-formyl peptides-induced neutrophil activation. Therefore, FPR1 is an important therapeutic target for drugs to treat septic or sterile inflammatory diseases. Honokiol, a major bioactive compound of Magnoliaceae plants, possesses several anti-inflammatory activities. Here, we show that honokiol exhibits an inhibitory effect on FPR1 binding in human neutrophils. Honokiol inhibited superoxide anion generation, reactive oxygen species formation, and elastase release in bacterial or mitochondrial N-formyl peptides (FPR1 agonists)-activated human neutrophils. Adhesion of FPR1-induced human neutrophils to cerebral endothelial cells was also reduced by honokiol. The receptor-binding results revealed that honokiol repressed FPR1-specific ligand N-formyl-Nle-Leu-Phe-Nle-Tyr-Lys-fluorescein binding to FPR1 in human neutrophils, neutrophil-like THP-1 cells, and hFPR1-transfected HEK293 cells. However, honokiol did not inhibit FPR2-specific ligand binding to FPR2 in human neutrophils. Furthermore, honokiol inhibited FPR1 agonist-induced calcium mobilization as well as phosphorylation of p38 MAPK, ERK, and JNK in human neutrophils. In conclusion, our data demonstrate that honokiol may have therapeutic potential for treating FPR1-mediated inflammatory diseases.
Highlights
Inflammation is a major feature of the host response against external pathogen invasion or internal pathologic progression
Honokiol (1, 3, and 10 μM) had dose-dependent inhibitory effects on superoxide anion generation and elastase release in human neutrophils activated by a bacterial Formyl peptide receptor 1 (FPR1) activator, N-formyl-Met-Leu-Phe, with IC50 values of 3.31 ± 0.52 and 4.16 ± 0.32 μM, respectively (Fig. 1A)
Honokiol (1, 3, and 10 μM) did not cause lactate dehydrogenase (LDH) release (Fig. 1E). These results suggested that its anti-inflammatory effects on neutrophil respiratory burst and degranulation were not due to superoxide anion scavenging or cytotoxicity
Summary
Inflammation is a major feature of the host response against external pathogen invasion or internal pathologic progression. Leukocyte activation and infiltration are expressions of the inflammatory and immune responses[1, 2]. Liu et al has reported that honokiol attenuated rat traumatic spinal cord injury through downregulation of Kruppel-like factor 4 expression and suppression of the inflammatory response[16]. FPR1 can attract neutrophils to inflammatory site and mediate intracellular signal transduction in immune responses[23, 24]. FPR1 activation leads to either infectious or sterile inflammation by recognizing bacterial or mitochondrial N-formyl peptides[25, 26]. We sought to elucidate the exact mechanism of honokiol-associated anti-inflammatory activity in human neutrophils. The present results showed that honokiol inhibits N-formyl peptide-induced superoxide anion generation, elastase release, and cell adhesion in human neutrophils
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