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

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. Cyclosporine (CsA) and FK‐506 inhibited IL‐13 synthesis, when cells were stimulated by TPA/ionomycin. However, stimulation by α‐CD3/α‐CD28 led to an enhanced IL‐13 synthesis. NF‐κB inhibitor N‐tosyl‐L‐lysine chloromethylketone (TLCK) inhibited IL‐13 synthesis more effectively after TPA/ionomycin stimulation. After α‐CD3/α‐CD28 stimulation, only 300 μM TLCK inhibited IL‐13 synthesis. Dexamethasone inhibited IL‐13 equally effective after α‐CD3/α‐CD28 and TPA/ionomycin stimulation. p38 MAPK inhibitor SB203580 inhibited IL‐13 synthesis only partially. MEK inhibitor U0126 inhibited TPA/ionomycin induced IL‐13 synthesis very effectively, whereas α‐CD3/α‐CD28 stimulated IL‐13 induction was resistant to this drug. These results were confirmed in purified CD4+ T cells. In difference to PBMCs α‐CD3/α‐CD28 stimulated IL‐13 synthesis was effectively inhibited by CsA, FK‐506 and U0126. 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%. 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. British Journal of Pharmacology (2002) 135, 1915–1926; doi:10.1038/sj.bjp.0704656