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

Abstract

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-γ 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-γ response to staphylococcal enterotoxin B was correlated to the lack of regular Vβ8+ T cells and Vβ8+ NK T cells, and the low IFN-γ 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-γ, 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.

Oral Administration of Lactic Acid Bacteria Isolated from Traditional South Asian Fermented Milk `Dahi' Inhibits the Development of Atopic Dermatitis in NC/Nga Mice

“…In NC/Nga mice, serum IgE suppression is reported to be comparatively difficult because they are insensitive to IL-12 compared with BALB/c mice (32,33). Hence it is possible that the R-037 administration could not suppress IgE elevation sufficiently in NC/Nga mice.…”

Activation of peroxisome proliferator‐activated receptor gamma suppresses mast cell maturation involved in allergic diseases

“…In pathological skin conditions, histamine is involved in the induction of itching, flaring and edema, and therefore, the contribution of activated mast cells are important (15,16). However, regulatory systems of mast cell maturation in allergic dermatitis are still unclear.…”

“…The murine-atopic dermatitis model was established according to a method previously (15). Spontaneous dermatitis similar to human atopic dermatitis was observed for 4-5 weeks.…”

“…Total RNA was extracted from the BMMCs, and first-strand cDNA was generated from 1 µg of RNA by using oligo (dT) [12][13][14][15][16][17][18] primer and SuperScriptIII RNase H Reverse Transcriptase (Invitrogen) according to the manufacturer's protocol. The reaction mixture was amplified with the oligonucleotides specific for HDC, MMCP-1, MMCP-2, MMCP-4 and β-actin (11-13).…”

Critical role of the liver CD8+ CD122+ T cells in the generalized Shwartzman reaction of mice

“…The liver MNC were prepared essentially as previously described [21,45,46]. Briefly, the livers were minced and suspended in HBSS containing 0.05% collagenase (Wako, Osaka, Japan), and then were shaken for 20 min in a 37 C water bath.…”