Hyperresponsive TH2 cells with enhanced nuclear factor-kappa B activation induce atopic dermatitis-like skin lesions in Nishiki-nezumi Cinnamon/Nagoya mice.

Abstract

BACKGROUND: Nishiki-nezumi Cinnamon/Nagoya (NC/Nga) mice raised in nonair-controlled conventional circumstances spontaneously develop atopic dermatitis-like skin lesions; however, the underlying mechanisms remain unclear. OBJECTIVE: We wanted to identify the critical intracellular signaling molecules in T cells that induce atopic dermatitis-like skin legions in NC/Nga mice. METHODS: We examined the levels of signal transduction and cytokine production in T cells, particularly those in atopic dermatitis-like lesions induced by the topical injection of mite antigens in NC/Nga mice under specific pathogen-free conditions. RESULTS: In NC/Nga mice maintained under specific pathogen-free conditions, the capability of T(H)1/T(H)2 and T cytotoxic 1/T cytotoxic 2 (Tc1/Tc2) cell differentiation increased significantly. T-cell antigen receptor-mediated activation of the extracellular signal-regulated kinase/mitogen-activated protein kinase cascade and nuclear factor-kappaB (NF-kappaB) signaling were enhanced in NC/Nga T cells. The expression of T(H)2 cytokines (IL-4, IL-13, and IL-5) and that of GATA-binding protein 3 (GATA3), avian musculoaponeurotic fibrosarcoma (c-Maf), NF-kappaB, and activator protein 1 (AP1) selectively increased in draining lymph node T cells of NC/Nga mice. Moreover, the cell transfer of inhibitory NF-kappaB mutant-infected T(H)2 cells reduced ear thickness in the mite antigen-induced skin lesion of NC/Nga mice. CONCLUSION: Hyperresponsive T(H)2 cells with an enhanced activity of NF-kappaB and AP1 play a crucial role in the pathogenesis of atopic dermatitis-like skin lesions in NC/Nga mice. CLINICAL IMPLICATIONS: These results indicate potential therapeutic usefulness of developing selective inhibitors for NF-kappaB in the treatment of human atopic dermatitis.