1 IL-13 is an important mediator in in¯ammatory diseases such as asthma. IL-13 is mainly produced by T cells. However, signalling pathways leading to induction of this cytokine are not wellcharacterized. 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 a-CD3/a-CD28 led to an enhanced IL-13 synthesis. 3 NF-kB inhibitor N-tosyl-L-lysine chloromethylketone (TLCK) inhibited IL-13 synthesis more eectively after TPA/ionomycin stimulation. After a-CD3/a-CD28 stimulation, only 300 mM TLCK inhibited IL-13 synthesis. Dexamethasone inhibited IL-13 equally eective after a-CD3/a-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 eectively, whereas a-CD3/a-CD28 stimulated IL-13 induction was resistant to this drug. 5 These results were con®rmed in puri®ed CD4 + T cells. In dierence to PBMCs a-CD3/a-CD28 stimulated IL-13 synthesis was eectively inhibited by CsA, FK-506 and U0126. 6 Therefore U0126 was tested in an animal model of allergic asthma. We could demonstrate for the ®rst time that inhibition of the MEK ± ERK cascade is a therapeutic option for asthma. Intraperitoneal administration of 10 mg kg 71 U0126 reduced lung eosinophilia in ovalbuminchallenged Brown Norway rats by 44%. 7 These results demonstrate that dierent 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.