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

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-κB (NF-κB) 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-κB, and activator protein 1 (AP1) selectively increased in draining lymph node T cells of NC/Nga mice. Moreover, the cell transfer of inhibitory NF-κB 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-κB 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-κB in the treatment of human atopic dermatitis.