Tryptanthrin reduces mast cell proliferation promoted by TSLP through modulation of MDM2 and p53

Atopic dermatitis (AD) results from complex interactions between mast cells and inflammatory mediators. An inflammatory mediator, thymic stromal lymphopoietin (TSLP) is known to promote mast cell proliferation through up-regulation of mouse double minute 2 (MDM2, a negative regulator of p53) and aggravate AD. In this study, we investigated whether tryptanthrin (TR, an anti-inflammatory agent) would regulate TSLP-induced mast cell proliferation and TSLP-induced a pro-inflammatory cytokine, tumor necrosis factor (TNF)-α production from mast cells.

Human mast cell line (HMC-1) cells were treated with TR and stimulated with TSLP. Proliferation was measured with a bromodeoxyuridine incorporation assay. And pro- and anti-apoptotic factors were analyzed with quantitative real-time PCR, Western blot analysis, and ELISA. The mRNA expression and production of TNF-α were analyzed with quantitative real-time PCR and ELISA.

TR significantly inhibited the proliferation of HMC-1 cells promoted by TSLP. TR inhibited MDM2 expression, whereas TR increased the expression of p53, poly ADP-ribose polymerase, and caspase-3 in the TSLP-stimulated HMC-1 cells. TR significantly inhibited Ki67 mRNA expression as well as mRNA expression and production of interleukin (IL)-13 in the TSLP-stimulated HMC-1 cells. Moreover, TR significantly suppressed mRNA expression and production of TNF-α in the TSLP-stimulated HMC-1 cells. Finally, the mRNA expression of IL-7 receptor α chain and TSLP receptor was inhibited by TR in the TSLP-stimulated HMC-1 cells.

Our results suggest that TR determined with new concept has intensive potential for the treatment of mast cell-mediated allergic diseases, such as AD.