Suppression of airway inflammation by luteolin via upregulation of regulatory T cells

In recent study, we used a mouse model of airway inflammation to examine the suppressive activity of luteolin-induced CD4+CD25+ regulatory T cells in vivo. We studies provide compelling evidence that induction of Treg cell populations by luteolin treatment can facilitate the suppression of allergic inflammation and AHR through increased foxp3 and/or TGF-b1 production. Balb/c mice were sensitized with OVA and, upon OVA aerosol challenge, developed airway eosinophilia, mucus hypersecretion, elevation of OVA-specific IgE, Th2 cytokines and chemokine levels, up-regulation of eotaxin 2 or CCR3 expression, and airway hyperresponsiveness. Intraperitoneal administration of luteolin, identified from the root of Salvia plebeia R. Br, and cyclosporine A (CsA), significantly inhibited OVA-induced increases in immune cell counts, eosinophil counts, and IL-4, IL-5, IL-13, and eotaxin levels recovered in bronchoalveolar lavage fluid (BALF) in OVA-sensitized mice. Luteolin and CsA also substantially reduced the OVA-specific IgE, eotaxin 2 levels, and CCR3 expression of Bronchoalveolar lavage fluid (BALF). In contrast, luteolin also substantially (p < 0.05, p < 0.01) increased the IL-10, IFN-g level, and IL-10 or TGF-b1 mRNA expression of BALF. Histological studies showed that luteolin and CsA dramatically inhibited eosinophilia, and infiltration lymphocytes in lung tissues. An in vitro also, CD4+CD25- T cells of luteolin treatment contained elevated numbers of luteolin-induced CD4+CD25+ Treg (ciTreg) cells, higher TGF-b1 and Foxp3 mRNA expression, and produced strong interleukin-2, IL-10, TGF-b response. Transfer of ciTreg cells to OVA-sensitized mice reduced airway hyperreactivity (AHR), recruitment of eosinophils, eotaxin, IgE, and T helper type 2 (Th2) cytokine expression, and increased the IFN-g production in the BALF after allergen challenge, and significantly improved pathologic lesion scores of the lungs. Furthermore, adoptive transfer of ciTreg cells prevented disease in a CD25-depleted mouse asthma model. These studies show that immune suppression via the induction of foxp3 and CD4+CD25+ Treg cells may represent a new strategy in the development of therapies for managing asthma and other inflammatory diseases.