Reduced interferon-gamma production and mutations of the interleukin-12 receptor beta(2) chain gene in atopic subjects.
BACKGROUND
The atopic patient has a predisposition to selective synthesis of IgE antibodies to common environmental antigens. IgE production is upregulated by interleukin-4 (IL-4) and downregulated by interferon-gamma (IFN-gamma). IL-12 is a cytokine that induces IFN-gamma production. The signal of IL-12 is transduced through the IL-12 receptor (IL-12R) and Stat4.


METHODS
We examined IFN-gamma production in peripheral blood mononuclear cells (PBMCs) following stimulation with IL-12 or phytohemagglutinin (PHA) in healthy controls and atopic patients. Moreover, sequences of the IL-12R beta(2) chain gene were analyzed.


RESULTS
The serum IgE levels were negatively correlated (p < 0.001) with IFN-gamma production. In 24 out of 75 atopic patients, IFN-gamma production in PBMCs following stimulation with IL-12 was under the detection limit, but PHA stimulation elicited detectable IFN-gamma production. Sequence analysis of the cDNA of IL-12R beta(2) revealed three kinds of distinct genetic mutations (2496 del 91, 1577 A to G and 2799 A to G) in 10 unrelated subjects of the 24 whose IFN-gamma production following IL-12 stimulation was under the detection limit. PBMCs cultured with IL-12 and PHA in these 10 subjects showed decreased tyrosine phosphorylation of Stat4.


CONCLUSIONS
The results of our study indicate that atopic diseases are caused, in part, by impairment of the IL-12 signal cascade, which downregulates IgE production, and that the mutation of the IL-12R beta(2) chain gene is one of the causative genes for atopy.
Kondo
N
N
Department of Pediatrics, Gifu University School of Medicine, Gifu, Japan. nkondo@cc.gifu-u.ac.jp
Matsui
E
E
Kaneko
H
H
Fukao
T
T
Teramoto
T
T
Inoue
R
R
Watanabe
M
M
Kasahara
K
K
Morimoto
N
N
D002478:Cells, Cultured; D020022:Genetic Predisposition to Disease; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000235:genetics* / Q000276:immunology*; D007073:Immunoglobulin E / Q000096:biosynthesis; D007371:Interferon-gamma / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D018448:Models, Immunological; D009154:Mutation; D018123:Receptors, Interleukin / Q000235:genetics*; D053707:Receptors, Interleukin-12; D015398:Signal Transduction
D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D018664:Interleukin-12; D007073:Immunoglobulin E; D007371:Interferon-gamma