In atopic patients, allergen-specific T cells have acquired the Th2 phenotype, and secrete IL-4, IL-5, IL-13, but no IFNgamma. IL-4 and IL-13 independently induce a class switch to IgE antibodies in B cells. Crosslinking of surface IgE on mast cells and basophils by the allergen causes the release of histamine in large quantities. We examined the effect of histamine on IL-12 production in whole blood cultures, because IL-12 is essential for Th1 development (mainly by its strong potential to induce IFNgamma) and inhibits induction of Th2 responses. Histamine, at physiological concentrations, strongly inhibits human IL-12 p40 (inactive monomer) and p70 (bioactive heterodimer) mRNA and protein production by human monocytes. Specific histamine receptor antagonists revealed that this inhibition is mediated via the H2 receptor and induction of intracellular cAMP. The inhibition of IL-12 production is independent of IL-10 and IFNgamma. The observation that histamine strongly reduces the production of the Th1-inducing cytokine IL-12 implies a positive feedback mechanism for the development of Th2 responses in atopic patients.
In addition, we examined the in vitro production of IL-4 and IL-13 by peripheral blood T cells from allergic asthma patients and non-atopic controls. IL-4 and IL-13 have many overlapping functions, but the regulation of production of these cytokines is entirely different. T-cell receptor triggering provides a positive as well as a negative signal for IL-13 production. T cells are optimally stimulated for the production of IL-13 with anti-CD28 and PMA. The negative signal is delivered by an additional calcium-inducing stimulus (Ca-ionophore, anti-CD2, or anti-CD3) and can be reversed by cyclosporin A (CsA). IL-4 production requires a T cell receptor signal and is inhibited by CsA. In T cells from allergic asthma patients, this negative signal for IL-13 production is reduced. For IL-4 production we found no differences between patients and healthy controls. Because IL-13 is located on chromosome 5q31, a region associated with allergic asthma, we hypothesized that an alteration in the IL-13 promoter could be responsible for this effect. Indeed, such an IL-13 promoter polymorphism was identified and it is associated with altered IL-13 production, allergic asthma, and increased binding of nuclear proteins. These findings are particularly interesting in light of the recent observation that IL-13 is playing a key role in the effector phase of asthma in mice. |
