299 IL-31/IL-31 receptor alpha interaction augments IL-4-induced Ccl 17 and Ccl 22 production in dendritic cells

Abstract

One of characteristic features of atopic dermatitis (AD) is severe pruritus that is closely related to disease activity. Recent studies have shown that IL-31 is one of key determinants of pruritus in AD. Furthermore, anti-IL-31 receptor alpha (IL-31RA) antibody treatment has been reported to show a clinical improvement of pruritus. Therefore, IL-31 has been thought to be an important cytokine to regulate pruritus and disease activity in AD; however, how IL-31 is involved in the immune response in AD has been largely unknown. Epidermal Langerhans cells (LCs) and dermal dendritic cells (DCs) derived from bone marrow cells have been reported to play a critical role in the pathogenesis of AD. LCs and DCs produce Ccl 17 and Ccl 22 that chemoattracts Th2 cells, which leads to the development of AD. Therefore, we aimed to clarify how IL-31/IL-31RA interaction affects functions of DCs including production of Ccl 17 and Ccl 22. To investigate this, we analyzed murine bone marrow derived-DCs (BMDCs) stimulated with IL-4. We found that IL-31RA expression was upregulated by IL-4 stimulation in a dose-dependent manner in BMDCs. Furthermore, IL-4 upregulated production of Ccl 17 and Ccl 22, which was enhanced by IL-31, whereas IL-31 alone did not produce them. These data suggest that IL-4 mediates IL-31RA expression and IL-31/IL-31RA interaction augments production of Ccl 17 and Ccl 22 in BMDC, which promotes Th2-deviated immune response in AD. Since we have previously reported that soy bean tar Glyteer, an aryl hydrocarbon receptor (AHR) ligand, impairs IL-4/Stat 6 signaling in BMDCs, we examined whether Glyteer affected IL-31RA expression induced by IL-4 stimulation. Glyteer inhibited upregulation of IL-31RA expression induced by IL-4 in a dose-dependent manner. Also, Glyteer inhibited production of Ccl 17 and Ccl 22 induced by IL-4 and IL-31. Taken together, these data suggest a possibility that treatment using AHR activators such as Glyteer and anti- IL-31RA antibody may synergistically improve pruritus and disease activitity of AD.