The PGI2 Analog Cicaprost Inhibits IL-33–Induced Th2 Responses, IL-2 Production, and CD25 Expression in Mouse CD4+ T Cells

Abstract

IL-33 has pleiotropic functions in immune responses and promotes the development of allergic diseases and asthma. IL-33 induces Th2 differentiation and enhances type 2 cytokine production by CD4⁺ T cells. However, the regulation of IL-33-driven type 2 cytokine responses is not fully defined. In this study, we investigated the effect of PGI₂, a lipid mediator formed in the cyclooxygenase pathway of arachidonic acid metabolism, on naive CD4⁺ T cell activation, proliferation, and differentiation by IL-33. Using wild-type and PGI₂ receptor (IP) knockout mice, we found that the PGI₂ analog cicaprost dose-dependently inhibited IL-33-driven IL-4, IL-5, and IL-13 production by CD4⁺ T cells in an IP-specific manner. In addition, cicaprost inhibited IL-33-driven IL-2 production and CD25 expression by CD4⁺ T cells. Furthermore, IP knockout mice had increased IL-5 and IL-13 responses of CD4⁺ T cells to <i>Alternaria</i> sensitization and challenge in mouse lungs. Because IL-33 is critical for <i>Alternaria-</i>induced type 2 responses, these data suggest that PGI₂ not only inhibits IL-33-stimulated CD4⁺ Th2 cell responses in vitro but also suppresses IL-33-induced Th2 responses caused by protease-containing allergens in vivo.