Research and Development Focused on Anti-allergy and Immunomodulatory Drugs Targeting Thymic Stromal Lymphopoietin

Abstract

Thymic stromal lymphopoietin (TSLP) is a key cytokine produced primarily by epithelial cells that induces a Th2-type immune response. We have studied the regulation of TSLP production by low-molecular-weight compounds and proposed their use as immunoregulators. Several compounds, including xylene, nonanoic acid, and valeric acid, induce TSLP production. Painting mouse skin with xylene enhanced ovalbumin-specific immunoglobulin E (IgE) production, indicating that environmental pollutants that induce TSLP production may enhance the evocation of allergic responses. By contrast, retinoic acid, which strongly induces TSLP production, can enhance immunoglobulin G (IgG) production against influenza HA antigen in mice, indicating that TSLP inducers can serve as chemical adjuvants. During our analyses of the regulation of TSLP expression, we found that TSLP production was reduced under hypoxic conditions in response to increased hypoxia inducible factor (HIF)-1 levels. We also found that HIF proline hydroxylase inhibitors, which stabilize HIF-1, can inhibit TSLP production, and identified a novel TSLP production inhibitor in a chemical library screen. This compound inhibits TSLP production in vitro and in vivo. The target of this inhibitors a bromodomain and extraterminal (BET) family protein. BET family proteins are thus potential therapeutic targets for allergic diseases. In conclusion, TSLP is a unique cytokine produced by epithelial cells that is regulated with low-molecular-weight compounds. Regulators of TSLP production by epithelial cells may serve as novel antiallergic drugs and/or chemical adjuvants.