Abstract
Severe pruritus is a characteristic feature of atopic dermatitis (AD) and is closely related to its activity. Recent studies have shown that IL-31 is a key determinant of pruritus in AD. Anti-IL-31 receptor alpha (IL-31RA) antibody treatment has also been reported to improve pruritus clinically, subsequently contributing to the attenuation of AD disease activity. Therefore, IL-31 has been thought to be an important cytokine for regulating pruritus and AD disease activity; however, how IL-31 is involved in the immune response in AD has remained 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 AD pathogenesis. LCs and DCs produce Ccl 17 and Ccl 22, which chemoattract Th2 cells, leading to AD development. Therefore, we aimed to clarify how IL-31/IL-31RA interaction affects Ccl 17 and Ccl 22 production. To test this, we analyzed murine bone marrow-derived DCs (BMDCs) stimulated with IL-4, an important cytokine in AD development. We found that IL-31RA expression was upregulated by IL-4 stimulation in a dose-dependent manner in BMDCs. Furthermore, IL-31 upregulates Ccl 17 and Ccl 22 production in the presence of IL-4, whereas IL-31 stimulation alone did not produce Ccl 17 and Ccl 22. These findings suggest that IL-4 mediates IL-31RA expression and IL-31/IL-31RA interaction augments Ccl 17 and Ccl 22 production in BMDCs, which promotes Th2-deviated immune response in AD. Since we previously reported that soybean tar Glyteer, an aryl hydrocarbon receptor (AHR) ligand, impairs IL-4/Stat 6 signaling in BMDCs, we examined whether Glyteer affects IL-31RA expression induced by IL-4 stimulation. Glyteer inhibited upregulation of IL-31RA expression induced by IL-4 stimulation in a dose-dependent manner. Glyteer also inhibited Ccl 17 and Ccl 22 production induced by IL-4 and IL-31 stimulation. Taken together, these findings suggest that Glyteer treatment may improve AD disease activity by impairing IL-31/IL-31RA interaction in DCs.
Highlights
Interleukin (IL)-31 is a four-helix bundle cytokine closely related to the IL-6 cytokine family [1]
We first examined whether IL-4 stimulation upregulated IL-31 receptor alpha (IL-31RA) expression in bone marrow-derived DCs (BMDCs)
Quantitative reverse-transcription analysis revealed that IL-4 stimulation upregulated IL-31RA expression at the mRNA level in a dose-dependent manner (Figure 1a)
Summary
Interleukin (IL)-31 is a four-helix bundle cytokine closely related to the IL-6 cytokine family [1]. The lesional skin of AD exhibits Th2-deviated immune reactions such as those involving IL-4, IL-5, and IL-13, which contribute to the development of this disease [5]. A recent study has shown that anti-IL-31 receptor alpha (IL-31RA) antibody treatment using nemolizumab produced clinical improvement of pruritus, subsequently contributing to the attenuation of AD disease activity [7]. The mechanism behind this is still not fully understood, but it has been shown that IL-31RA is expressed on sensory neurons and IL-31 derived from activated T cells under Th2-skewed conditions stimulates IL-31RA on sensory nerves, resulting in severe pruritus in AD [8]. IL-31/IL-31RA interaction is deeply involved in AD disease activity in addition to pruritus
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