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The Mechanism of a Defective IFN- Response to Bacterial Toxins in an Atopic Dermatitis Model, NC/Nga Mice, and the Therapeutic Effect of IFN-, IL-12, or IL-18 on Dermatitis¹

Yoshiko Habu^*, Shuhji Seki^2,*, Eiji Takayama^*, Takashi Ohkawa, Yuji Koike, Katsunori Ami^*, Takashi Majima and Hoshio Hiraide^*

^* Division of Basic Traumatology, National Medical Department of Pediatrics, and Department of Surgery I, National Defense Medical College Research Institute, Tokorozawa, Japan

NC/Nga (NC) mice raised under conventional conditions (Conv. NC mice) spontaneously develop dermatitis similar to human atopic dermatitis, whereas NC mice raised under the specific pathogen-free conditions do not develop dermatitis. In the present study, we show that the representative Th1 cytokine, IFN- levels in the sera of NC mice, injected with either staphylococcal enterotoxin B or endotoxin (LPS), to be severalfold lower than those of normal mice. The low IFN- response to staphylococcal enterotoxin B was correlated to the lack of regular V8⁺ T cells and V8⁺ NK T cells, and the low IFN- response to LPS was correlated to an impaired IL-18 production of macrophages. The CD3-stimulated IL-4 production from liver and spleen T cells from Conv. NC mice in vitro was greatly augmented. The serum IL-4 levels of untreated Conv. NC mice also were higher than those of normal mice and specific pathogen-free NC mice. Treatment of Conv. NC mice either with IFN-, IL-12, or IL-18 twice a week from 4 wk of age substantially inhibited the elevation of the serum IgE levels, serum IL-4 levels, and dermatitis, and IL-12 or IL-18 treatment also reduced the in vitro IL-4 production from CD3-stimulated liver T cells. The systemic deficiency in the Th1 response to bacterial stimulation thus leads to a Th2-dominant state and may induce an abnormal cellular immune response in the skin accompanied with an overproduction of IgE and a susceptibility to dermatitis in NC mice.

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