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.
Pahl
Andreas
A
Department of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nürnberg, Fahrstr. 17, D-91054 Erlangen, Germany. pahl@pharmakologie.uni-erlangen.de
Zhang
Meixia
M
Kuss
Hildegard
H
Szelenyi
Istvan
I
Brune
Kay
K
D000818:Animals; D018927:Anti-Asthmatic Agents / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism*; D002070:Butadienes / Q000008:administration & dosage; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D007274:Injections, Intraperitoneal; D018793:Interleukin-13 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology; D050778:NFATC Transcription Factors; D009570:Nitriles / Q000008:administration & dosage; D009687:Nuclear Proteins; D011657:Pulmonary Eosinophilia / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011914:Rats, Inbred BN; D016559:Tacrolimus / Q000494:pharmacology; D013997:Time Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology
D018927:Anti-Asthmatic Agents; D002070:Butadienes; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D018793:Interleukin-13; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009570:Nitriles; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; C113580:U 0126; D016572:Cyclosporine; D020928:Mitogen-Activated Protein Kinases; D016559:Tacrolimus