Regulation of IL‐13 synthesis in human lymphocytes: implications for asthma therapy
A Pahl, M Zhang, H Kuss, I Szelenyi… - British journal of …, 2002 - Wiley Online Library
A Pahl, M Zhang, H Kuss, I Szelenyi, K Brune
British journal of pharmacology, 2002•Wiley Online LibraryIL‐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 …
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 …
- 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
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