Simvastatin Inhibits IL-5-Induced Chemotaxis and CCR3 Expression of HL-60-Derived and Human Primary Eosinophils

PLoS One. 2016 Jun 8;11(6):e0157186. doi: 10.1371/journal.pone.0157186. eCollection 2016.

Abstract

IL-5-induced chemotaxis of eosinophils is an important feature of allergic airway inflammatory diseases. Simvastatin, a lipid lowering agent, has been shown to exhibit anti-inflammatory and anti-allergic effects. Our aim was to investigate the effect of simvastatin on IL-5-induced eosinophil chemotaxis and its regulatory mechanisms. Eosinophils were derived by treating HL-60 clone 15 (HC15) cells with butyric acid (BA) in an alkaline condition or through direct isolation from human peripheral blood. The expressions of CC chemokine receptor 3 (CCR3) and interleukin (IL)-5 receptors (IL5Rα and β) were analyzed using RT/real-time PCR. The granular proteins were stained using fast green. Eotaxin-induced chemotaxis was measured using a transwell migration assay. CCR3 protein expression was revealed by immunocytochemistry. An animal model of allergic rhinitis was established by challenging Sprague-Dawley® rats repeatedly with ovalbumin. Butyric acid significantly increased the expression of IL5Rα and IL5Rβ, CCR3 and granular proteins in HC15 cells, indicating the maturation of eosinophils (BA-E cells). IL-5 further enhanced the CCR3 expression at both the mRNA and protein levels and the eotaxin-induced chemotaxis of BA-E cells. Simvastatin inhibited the effects of IL-5 on BA-E cells, but not in the presence of mevalonate. Similar results were also exhibited in human primary eosinophils. In vivo animal studies further confirmed that oral simvastatin could significantly suppress the infiltration of eosinophils into turbinate tissues of allergic rats. Therefore, simvastatin was demonstrated to inhibit IL-5-induced CCR3 expression and chemotaxis of eosinophils mediated via the mevalonate pathway. We confirmed that simvastatin also reduced eosinophilic infiltration in allergic rhinitis.

MeSH terms

  • Animals
  • Chemotaxis / drug effects*
  • Disease Models, Animal
  • Eosinophils / immunology*
  • Gene Expression Regulation / drug effects*
  • Gene Expression Regulation / immunology
  • HL-60 Cells
  • Humans
  • Interleukin-5 / immunology*
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, CCR3 / immunology*
  • Rhinitis, Allergic / chemically induced
  • Rhinitis, Allergic / immunology
  • Rhinitis, Allergic / pathology
  • Simvastatin / adverse effects
  • Simvastatin / pharmacology*

Substances

  • CCR3 protein, human
  • IL5 protein, human
  • Interleukin-5
  • Receptors, CCR3
  • Simvastatin

Grant support

This work was supported by grants from the Chang Gung Memorial Hospital (CMRPG392311 and CMRPG3C1941).