Study On The Efficacy And Mechanism Of 3'3-indolemethane In Atopic Dermatitis

Atopic dermatitis(AD)is a serious and chronically relapsing inflammatory skin disorder involving severe pruritus,dryness,and clinical manifestations like erythematous,edema,and lichenification in skin lesions.With a strongly genetic predisposition,AD is characterized by two distinct phases,the chronic and acute phases,resulting in either Thl or Th2 type of immune response.At present,the treatment of AD patients mainly employs drugs such as glucocorticoids,calcineurin inhibitors and cyclosporine A.Although these drugs have a good anti-inflammatory effect,they have poor patient compliance and long-term use will lead to many side effects.The 3'3-indolemethane(DIM)is a natural compound formed by condensation of indole-3-methanol(I3C)in the cruciferae brassica in the acidic environment of the digestive tract.Studies have shown that DIM not only has anti-tumor effects,but also can inhibit the inflammatory response and relieve symptoms of inflammatory diseases by inhibiting NF-?B signaling pathway and regulating T cell differentiation.Therefore,in this subject,we evaluate and explore the efficacy and mechanism of DIM in AD mice model.2,4-dinitrofluorobenzene(DNFB)and BALB/c mice were recruited to construct an acute AD mice model,whose disease characteristics were similar to those of human acute AD.After treatment with DIM via intraperitoneal injection,the efficacy was evaluated by skin appearance observation and the pathological/histological staining methods.In order to investigate the effect of DIM on the inflammatory cytokines in skin tissue of AD mice,we examined the changes of representative proteins of Th1,Th2,Th 17 and Treg cells in skin tissue after treatment to analyze the influence of DIM on T cell differentiation.The effect of DIM on the differentiation of Th2 cells was investigated at the cellular level as well.Thymic stromal lymphopoietin(TSLP)plays an important role in the development of AD which can induce maturation and migration of dendritic cells and promote Th2 cell differentiation.Thus,we examined the changes of TSLP in mouse skin tissue prior to and after treatment as an indicator of the efficacy of DIM.In addition,in vitro experiments were carried out to investigate the effects of DIM on the secretion of TSLP from HaCaT cells.The results showed that DIM can significantly alleviate the pathological skin injury on acute phase of AD.DIM could decrease the levels of Th2-related cytokines IL-4,IL-5 and IL-13 in the skin tissue and inhibit the expression of ER-? and GATA3,proteins related to Th2 cell differentiation,and the expression of Th17-related factor IL-17A and RORyt have also been significantly inhibited.Simultaneously,elevated levels of Treg characteristic proteins FoxP3 could be observed.In addition,in vivo and in vitro experiments have both shown that DIM can inhibit HaCaT cells secretion of TSLP,thereby alleviating the inflammatory response.In summary,our study suggests that DIM may reduce the further activation of immune response by inhibiting the secretion of TSLP from HaCaT cells.DIM via intraperitoneal injection can promote the differentiation of Treg cells and inhibit the activation of Th2 and Th17 cells to suppress AD-related immune response while not significantly affect the differentiation of Th1 cells.DIM have shown good effect on DNFB-induced AD mice in acute phase,providing a new kind of candidate drug to enrich the therapeutic strategies for AD patients of acute phase.However,further investigation is needed for dose optimization,administration routes,therapeutic mechanism and how to enhance its therapeutic specificity.