Thymic stromal lymphopoietin (TSLP) is a novel IL-7-like cytokine. Human TSLP (hTSLP) activates CD11+ dendritic cells (DCs) both to up-regulate MHC class II and costimulatory molecules CD40, CD80, and CD86 and to secrete the TH2-attracting chemokines TARC and MDC. TSLP-activated DCs induce the most marked antigen-specific CD4+, naive T-cell expansion, after which the T cells differentiate into TH2 effector cells that secrete high concentrations of interleukin (IL)-4, IL-5, IL-13, and tumor necrosis factor-alpha(TNF-alpha). hTSLP is mainly expressed by epithelial cells in allergic inflamed tissues. Our central hypothesis is that allergic insults caused by chemicals, microbes, and allergens initially trigger mucosal epithelial cells or skin keratinocytes, to produce TSLP. TSLP then activates Langerhans' cells (immature dendritic cells in epidermis), which migrate into the draining lymph nodes and prime allergen-specific na'fve T cells to expand and differentiate into proallergic TH2 effector cells. These TH2 effector T cells then produce IL-4, IL-5, and IL-13 that initiate an allergic inflammation by triggering immunoglobulin E (IgE) production, eosinophilia, and mucus production. Further investigation of the molecular mechanisms underlying the regulation of TSLP production by epithelial cells and TH2 differentiation induced by TSLP-activated DCs is essential for understanding the whole pathophysiological process underlying allergic responses, and hence for developing more effective therapies for allergic diseases.
The specific aims of this proposal are: 1. To identify the molecular triggers of TSLP production by epithelial cells and the association of these triggers with human allergic diseases; 2. To identify the molecular regulation of TSLP receptor (TSLPR) and IL-7Ralpha co-expression; 3. To elicidate the molecular mechanisms by which TSLP-activated DCs induce TH2 differentiation.
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