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.