Cytokines secreted by Th2 cells negatively regulate lymphangiogenesis (CAM3P.202)

Abstract

Abstract Abstract Lymphatic vessels (LVs) consist of a unidirectional network that absorbs protein-rich fluid from peripheral tissues and drains it into the venous circulation through a conduit system of collecting vessels, lymph nodes (LNs), and ducts. In addition to fluid homeostasis, LVs also play an important role in immune surveillance by regulating immune cell migration and antigen delivery to draining LNs. Previous study showed IFN-g, a major Th1 cell-associated cytokine, negatively regulates lymphangiogenesis. However, the effects of the Th2 cell cytokines, IL-4 and IL-13, are still unclear. To reveal this, by using mouse lymphatic endothelial cells (mLECs), human LECs (hLECs), and Prox-1-GFP transgenic mice, we investigated the effects of IL-4 and IL-13 on lymphangiogenesis. Here we show that treatment of mLECs and hLECs with IL-4 and Il-13 down-regulated expression of Prox-1, essential transcription factor expressed by LECs. IL-4 and IL-13 also inhibited tube formation by LECs in vitro. Similarly, LECs co-cultured with Th2 cells showed decreased tube formation, and this effect was fully restored by cytokine neutralization with anti-IL-4 and anti-IL-13 antibodies. Moreover, in vivo blockade of IL-4 and IL-13 increased not only the density of LVs, but also the function of LVs in the airways. Therefore, our findings indicate a novel anti-lymphangiogenic function for Th2 cells via production of IL-4 and IL-13.