Regulation of IL-13 synthesis in human lymphocytes: implications for asthma therapy.

1. IL-13 is an important mediator in inflammatory diseases such as asthma. IL-13 is mainly produced by T cells. However, signalling pathways leading to induction of this cytokine are not well-characterized. We analysed the regulation of IL-13 in human peripheral blood mononuclear cells and CD4(+) T cells. 2. Cyclosporine (CsA) and FK-506 inhibited IL-13 synthesis, when cells were stimulated by TPA/ionomycin. However, stimulation by alpha-CD3/alpha-CD28 led to an enhanced IL-13 synthesis. 3. NF-kappa B inhibitor N-tosyl-L-lysine chloromethylketone (TLCK) inhibited IL-13 synthesis more effectively after TPA/ionomycin stimulation. After alpha-CD3/alpha-CD28 stimulation, only 300 microM TLCK inhibited IL-13 synthesis. Dexamethasone inhibited IL-13 equally effective after alpha-CD3/alpha-CD28 and TPA/ionomycin stimulation. 4. p38 MAPK inhibitor SB203580 inhibited IL-13 synthesis only partially. MEK inhibitor U0126 inhibited TPA/ionomycin induced IL-13 synthesis very effectively, whereas alpha-CD3/alpha-CD28 stimulated IL-13 induction was resistant to this drug. 5. These results were confirmed in purified CD4(+) T cells. In difference to PBMCs alpha-CD3/alpha-CD28 stimulated IL-13 synthesis was effectively inhibited by CsA, FK-506 and U0126. 6. Therefore U0126 was tested in an animal model of allergic asthma. We could demonstrate for the first time that inhibition of the MEK - ERK cascade is a therapeutic option for asthma. Intraperitoneal administration of 10 mg kg(-1) U0126 reduced lung eosinophilia in ovalbumin-challenged Brown Norway rats by 44%. 7. These results demonstrate that different signalling pathways are involved in regulating IL-13 synthesis in primary human T cells. Characterizing highly potent inhibitors of IL-13 synthesis can be exploited to identify new drugs to treat immunological diseases such as asthma.