Immune Regulation of TNFAIP3 in Psoriasis through Its Association with Th1 and Th17 Cell Differentiation and p38 Activation
Yanyun Jiang, Wenming Wang, Xiaofeng Zheng, Hongzhong Jin
Abstract
Background . Psoriasis is an immune‐mediated chronic inflammatory skin disorder in which the dysregulation of immune cells plays an important role in its development. Tumor necrosis factor‐ (TNF‐) α antagonists affect the immune repertoire, while TNF‐ α ‐induced protein 3 (TNFAIP3) has a protective role against the deleterious effects of inflammation and participates in immune regulation. Objective . We investigated the immune regulation of TNFAIP3 in the pathogenesis of psoriasis and determined whether it is involved in the antipsoriatic effect of TNF‐ α antagonists. Methods . mRNA levels were evaluated in blood from patients with moderate‐to‐severe psoriasis. The effects of TNF‐ α antagonists were examined in a mouse imiquimod‐ (IMQ‐) induced psoriasis‐like dermatitis model. In the mouse model, TNFAIP3 mRNA expression was determined using RT‐PCR. Serum levels of IL‐17A, IL‐23, IFN‐ γ , TNF‐ α , phosphorylated ERK1/2, p38, and JNK were measured using ELISA. The proportion of Th1 and Th17 cells in mouse spleens was analyzed using flow cytometry. Results . mRNA expression levels of TNFAIP3 in the blood were significantly lower in patients with moderate and severe psoriasis (mean ± SD = 0.44 ± 0.25) compared with normal subjects (mean ± SD = 1.00 ± 0.82) ( P < 0.01). In the mouse model, IMQ downregulated TNFAIP3 expression levels, which were increased after TNF‐ α antagonist treatment ( P < 0.05). Serum levels of Th17 cytokines (IL‐17A and IL‐23) and Th1 cytokines (IFN‐ γ and TNF‐ α ) were significantly higher in the IMQ and IMQ/rat IgG1 groups compared with the control group, and the application of TNF‐ α antagonists significantly decreased the levels of inflammatory cytokines ( P < 0.01). Notably, phosphorylated p38 levels were increased in the IMQ and IMQ/rat IgG1 groups compared with the control group but were downregulated by treatment with TNF‐ α antagonists ( P < 0.05). Th1 and Th17 cells were significantly increased in the IMQ group compared with the control group ( P < 0.01). Conclusion . TNFAIP3 downregulation associated with Th1 and Th17 cell differentiation and p38 activation might contribute in part to the mechanism of immune dysfunction in psoriasis. TNF‐ α antagonists might partly exert their effects on psoriasis via this pathway.