Vitamin E forms inhibit IL-13/STAT6-induced eotaxin-3 secretion by up-regulation of PAR4, an endogenous inhibitor of atypical PKC in human lung epithelial cells

J Nutr Biochem. 2012 Jun;23(6):602-8. doi: 10.1016/j.jnutbio.2011.03.003. Epub 2011 Jul 20.

Abstract

Eotaxin-3 (CCL-26), a potent chemokine for eosinophil recruitment and contributing significantly to the pathogenesis of asthma, is secreted by lung epithelial cells in response to T helper 2 cytokines including interleukin 13 (IL-13). Here we showed that vitamin E forms, but not their metabolites, differentially inhibited IL-13-stimulated generation of eotaxin-3 in human lung epithelial A549 cells. The relative inhibitory potency was γ-tocotrienol (γ-TE) (IC50 ~15 μM)>γ-tocopherol, δ-tocopherol (IC50 ~25-50 μM)>α-tocopherol. Consistent with suppression of eotaxin, γ-TE treatment impaired IL-13-induced phosphorylation of STAT6, the key transcription factor for activation of eotaxin expression, and consequently blocked IL-13-stimulated DNA-binding activity of STAT6. In search of the upstream target of γTE by using inhibitor and siRNA approaches, we discovered that the atypical protein kinase C (aPKC) signaling, instead of classical PKC, p38 MAPK, JNK or ERK, played a critical role in IL-13-stimulated eotaxin generation and STAT6 activation. While showing no obvious effect on aPKC expression or phosphorylation, γ-TE treatment resulted in increased expression of prostate-apoptosis-response 4 (PAR4), an endogenous negative regulator of aPKCs. Importantly, γ-TE treatment led to enhanced formation of aPKC/PAR4 complex that is known to reduce aPKC activity via protein-protein crosstalk. Our study demonstrated that γ-TE inhibited IL-13/STAT6-activated eotaxin secretion via up-regulation of PAR4 expression and enhancement of aPKC-PAR4 complex formation. These results support the notion that specific vitamin E forms may be useful anti-asthmatic agents.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anti-Asthmatic Agents / pharmacology
  • Apoptosis Regulatory Proteins / genetics*
  • Apoptosis Regulatory Proteins / metabolism
  • Chemokine CCL26
  • Chemokines, CC / metabolism*
  • Chromans / pharmacology
  • Epithelial Cells / drug effects*
  • Humans
  • Interleukin-13 / antagonists & inhibitors*
  • Interleukin-13 / genetics
  • Interleukin-13 / metabolism
  • Phosphorylation
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism
  • STAT6 Transcription Factor / antagonists & inhibitors
  • STAT6 Transcription Factor / genetics*
  • STAT6 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Tocopherols / pharmacology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Up-Regulation
  • Vitamin E / analogs & derivatives
  • Vitamin E / pharmacology*
  • alpha-Tocopherol / pharmacology
  • gamma-Tocopherol / pharmacology
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Anti-Asthmatic Agents
  • Apoptosis Regulatory Proteins
  • CCL26 protein, human
  • Chemokine CCL26
  • Chemokines, CC
  • Chromans
  • Interleukin-13
  • STAT6 Transcription Factor
  • STAT6 protein, human
  • Transcription Factors
  • prostate apoptosis response-4 protein
  • Vitamin E
  • plastochromanol 8
  • gamma-Tocopherol
  • Protein Kinase C
  • p38 Mitogen-Activated Protein Kinases
  • alpha-Tocopherol
  • delta-tocopherol
  • Tocopherols