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 upreg ulated by interleukin-4 (IL-4) a nd down regulated 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. Metho ds:We examined IFN-gamma production in peripheral blood mononuclear cells ( PBMCs) following stimulation with IL-12 or phytohemagglutinin (PHA) in heal thy controls and atopic patients. Moreover, sequences of the IL-12R beta (2 ) chain gene were analyzed. Results: The serum IgE levels were negatively c orrelated (p < 0.001) with IFN-<gamma> production. In 24 out of 75 atopic p atients, IFN-gamma production in PBMCs following stimulation with IL-12 was under the detection limit, but PHA stimulation elicited detectable IFN-gam ma production. Sequence analysis of the cDNA of IL-12R beta (2) revealed th ree 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 follo wing IL-12 stimulation was under the detection limit. PBMCs cultured with I L-12 and PHA in these 10 subjects showed decreased tyrosine phosphorylation of Stat4. Conclusions: The results of our study indicate that atopic disea ses are caused, in part, by impairment of the IL-12 signal cascade, which d ownregulates IgE production, and that the mutation of the IL-12R beta (2) c hain gene is one of the causative genes for atopy. Copyright (C) 2001 S. Ka rger AG, Basel.