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

• Published in: The Journal of nutritional biochemistry 2011-07, 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
• 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 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-PAR-4 complex formation. These results support the notion that specific vitamin E forms may be useful anti-asthmatic agents.