Quercetin inhibits histamine-induced calcium influx in human keratinocyte via histamine H4 receptors

Int Immunopharmacol. 2021 Jul:96:107620. doi: 10.1016/j.intimp.2021.107620. Epub 2021 Apr 13.

Abstract

Histamine is released from mast cells when tissues are inflamed or stimulated by allergens. Activation of histamine receptors and calcium influx via TRPV1 could be related to histamine-induced itch and skin inflammation. Quercetin is known to have anti-inflammatory and anti-itching effects. This study aims to understand whether quercetin can directly affect histamine-induced calcium influx in human keratinocyte. In it, we investigated quercetin, which acts on histamine-induced intracellular free calcium ([Ca2+]i) elevation in human keratinocyte. Changes in [Ca2+]i were measured using spectrofluorometry and confocal Imaging. We detected the expression of IL-8 after treatment of quercetin using qRT-PCR and evaluated its anti-itching effect in BALB/c mice. We also performed a docking study to estimate the binding affinity of quercetin to H4 receptors. We found that quercetin pretreatment decreased histamine-induced [Ca2+]i elevation in a concentration-dependent manner. The inhibitory effect of quercetin on histamine-induced [Ca2+]i elevation was blocked by JNJ7777120, a selective H4 antagonist, as well as by U73122, a PLC inhibitor, and by GF109203X, a PKC inhibitor. We also found that H4 agonist (4-methylhistamine)-induced [Ca2+]i elevation could be inhibited by quercetin. Moreover, the selective TRPV1 blocker capsazepine significantly suppressed the quercetin-mediated inhibition of histamine-induced [Ca2+]i elevation, whereas the TRPV4 blocker GSK2193874 had no effect. Last, quercetin decreased histamine and H4 agonist-induced IL-8 expression in keratinocyte and inhibited the scratching behavior-induced compound 48/80 in BALB/c mice. The molecular docking study also showed that quercetin exhibited high binding affinities with H4 receptors (autodock scores for H4 = -8.7 kcal/mol). These data suggest that quercetin could decrease histamine 4 receptor-induced calcium influx through the TRPV1 channel and could provide a molecular mechanism of quercetin in anti-itching, anti-inflammatory, and unpleasant sensations.

Keywords: Calcium influx; Histamine; Histamine 4 receptor; Quercetin; TRPV1.

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Calcium / metabolism*
  • Capsaicin / analogs & derivatives
  • Capsaicin / pharmacology
  • Choline Kinase / antagonists & inhibitors
  • Enzyme Inhibitors / pharmacology
  • Histamine / pharmacology*
  • Histamine / therapeutic use
  • Humans
  • Indoles / pharmacology
  • Interleukin-8 / genetics
  • Interleukin-8 / metabolism
  • Keratinocytes / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Molecular Docking Simulation
  • Molecular Structure
  • Piperazines / pharmacology
  • Piperidines / pharmacology
  • Primary Cell Culture
  • Pruritus / chemically induced
  • Pruritus / drug therapy
  • Quercetin / chemistry
  • Quercetin / pharmacology*
  • Quercetin / therapeutic use
  • Quinolines / pharmacology
  • Receptors, Histamine H4 / agonists
  • Receptors, Histamine H4 / antagonists & inhibitors
  • Receptors, Histamine H4 / chemistry
  • Receptors, Histamine H4 / metabolism*
  • TRPV Cation Channels / antagonists & inhibitors
  • Type C Phospholipases / antagonists & inhibitors

Substances

  • CXCL8 protein, human
  • Enzyme Inhibitors
  • GSK2193874
  • Indoles
  • Interleukin-8
  • Piperazines
  • Piperidines
  • Quinolines
  • Receptors, Histamine H4
  • TRPV Cation Channels
  • TRPV1 protein, human
  • TRPV4 protein, human
  • 1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine
  • Histamine
  • Quercetin
  • Choline Kinase
  • Type C Phospholipases
  • capsazepine
  • Capsaicin
  • Calcium