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

• Published in: The Journal of nutritional biochemistry 2012-06, Vol.23 (6), p.602-608
• Main Authors: Wang, Yun, Moreland, Michelle, Wagner, James G., Ames, Bruce N., Illek, Beate, Peden, David B., Jiang, Qing
• Format: Article
• Language: English
• Subjects: alpha-Tocopherol - pharmacology; Anti-Asthmatic Agents - pharmacology; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Asthma; Biological and medical sciences; Chemokine CCL26; chemokines; Chemokines, CC - secretion; Chromans - pharmacology; epithelial cells; Epithelial Cells - drug effects; Feeding. Feeding behavior; Fundamental and applied biological sciences. Psychology; gamma-Tocopherol - pharmacology; Humans; Inflammation; inhibitory concentration 50; Interleukin-13 - antagonists & inhibitors; Interleukin-13 - genetics; Interleukin-13 - metabolism; interleukins; metabolites; mitogen-activated protein kinase; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; pathogenesis; Phosphorylation; protein kinase C; Protein Kinase C - genetics; Protein Kinase C - metabolism; recruitment; secretion; Signal Transduction - drug effects; small interfering RNA; STAT6 Transcription Factor - antagonists & inhibitors; STAT6 Transcription Factor - genetics; STAT6 Transcription Factor - metabolism; Tocopherol; Tocopherols - pharmacology; Tocotrienol; transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Up-Regulation; Vertebrates: anatomy and physiology, studies on body, several organs or systems; vitamin E; Vitamin E - analogs & derivatives; Vitamin E - pharmacology
• ISSN: 0955-2863; 1873-4847
• DOI: 10.1016/j.jnutbio.2011.03.003

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.