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Unidad de Investigacion, Hospital San Pedro de Alcantara, Caceres, Spain
IL-4 is involved in several human diseases including allergies, autoimmunity, and cancer. Its effects are mainly mediated through the transcription factor STAT6. Therefore, investigation of compounds that regulate STAT6 activation is of great interest for these diseases. Natural polyphenols are compounds reported to have therapeutic properties in diseases involving IL-4 and STAT6. The aim of this study was to investigate the effect of these compounds in the activation of this transcription factor. We found that in hemopoietic cells from human and mouse origin, some flavonoids were able to inhibit the activation of STAT6 by IL-4. To identify molecular mechanisms, we focused on kaempferol, the compound that showed the greatest inhibitory effect with the lowest cell toxicity. Treatment of cells with kaempferol did not affect activation of Src kinase by IL-4 but did prevent the phosphorylation of JAK1 and JAK3. Further enzymatic analysis demonstrated that kaempferol blocked the in vitro phosphorylation activity of JAK3 without affecting JAK1, suggesting that it specifically targeted JAK3 activity. Accordingly, kaempferol had no effect on STAT6 activation in nonhemopoietic cell lines lacking JAK3, supporting its selective inhibition of IL-4 responses through type I receptors expressing JAK3 but not type II lacking this kinase. The inhibitory effect of kaempferol was also observed in IL-2 but not IL-3-mediated responses and correlated with the inhibition of MLC proliferation. These findings reveal the potential use of kaempferol as a tool for selectively controlling cell responses to IL-4 and, in general, JAK3-dependent responses.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by Fondo de Investigacion Sanitaria Grants 02/1150, and Junta de Extremadura Grant 2PR03A007. J.R.C. was supported by Fondo de Investigacion Sanitaria Grant 02/1150, M.P.-G. by the Fundacion Fernando Valhondo Calaff, and M.D.R. and J.Z. by the Subdireccion General de Investigacion Sanitaria, Exp. CA06/0110 and 99/3082.
2 Address correspondence and reprint requests to Dr. Jose Zamorano, Unidad de Investigacion, Hospital San Pedro de Alcantara, Avenida Pablo Naranjo s/n, 10003 Caceres, Spain. E-mail address: jose.zamorano{at}ses.juntaex.es
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