Phytochemical inhibition of interleukin-4-activated Stat6 and expression of VCAM-1.
Cellular functions induced by cytokine interleukin (IL)-4 and IL-4 signaling through signal transducer and activator of transcription (Stat)6 typify a Th2-type immune response. We investigated the inhibitor effect of the NFkappaB blocker parthenolide in the late-phase, Th2-type immune response. Parthenolide blocked by 90.6 +/- 7.4% the IL-4-induced expression of the endothelial vascular cell adhesion molecule (VCAM)-1, a hallmark of extravasation of very late antigen-4-positive leukocytes. The noncytotoxic concentrations of 10 microM parthenolide left a section of the IL-4 receptor signal transduction intact. Parthenolide did not interfere with the immediate IL-4-induced phosphorylation of endothelial Stat6 on its tyrosine residue Y641 and with tyrosine phosphorylation of the adapter molecule, Jak2-both processes are obligatory for dimerization and nuclear translocation of Stat6. But parthenolide inhibited the Stat6 DNA-binding activity in IL-4-stimulated endothelial cells and inhibited the IL-4-driven activation of a luciferase reporter gene under the control of Stat6-responsive elements (IC(50) 5.11 +/- 0.67 microM). Together, these data suggest an anti-chronic disease profile for the sesquiterpene lactone parthenolide.
Schnyder
Bruno
B
Biomedical Research Foundation, Institute for Biopharmaceutical Research Inc., Matzingen, Switzerland. bruno.schnyder@unifr.ch
Schnyder-Candrian
Silvia
S
Panski
Andreas
A
Bömmel
Heike
H
Heim
Markus
M
Duschl
Albert
A
Moser
René
R
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017930:Genes, Reporter / Q000187:drug effects; D006801:Humans; D039041:Integrin alpha4beta1; D016023:Integrins / Q000096:biosynthesis; D015847:Interleukin-4 / Q000494:pharmacology*; D053614:Janus Kinase 2; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D010766:Phosphorylation / Q000187:drug effects; D010936:Plant Extracts / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D016201:Receptors, Lymphocyte Homing / Q000096:biosynthesis; D050800:STAT6 Transcription Factor; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000037:antagonists & inhibitors*; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D039041:Integrin alpha4beta1; D016023:Integrins; D016328:NF-kappa B; D010936:Plant Extracts; D011518:Proto-Oncogene Proteins; D016201:Receptors, Lymphocyte Homing; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D012717:Sesquiterpenes; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D019010:Vascular Cell Adhesion Molecule-1; D015847:Interleukin-4; C002669:parthenolide; D004247:DNA; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2