Abstract
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.
(c)2002 Elsevier Science (USA).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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B-Lymphocytes / cytology
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B-Lymphocytes / drug effects
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B-Lymphocytes / metabolism
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Cell Line
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DNA / metabolism
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Dose-Response Relationship, Drug
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Endothelium, Vascular / cytology
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / metabolism
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Genes, Reporter / drug effects
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Humans
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Integrin alpha4beta1
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Integrins / biosynthesis
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Interleukin-4 / pharmacology*
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Janus Kinase 2
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Leukocytes / drug effects
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Leukocytes / metabolism
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Mice
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NF-kappa B / antagonists & inhibitors
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Phosphorylation / drug effects
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Plant Extracts / pharmacology*
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Protein Binding / drug effects
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins*
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Receptors, Lymphocyte Homing / biosynthesis
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STAT6 Transcription Factor
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Sesquiterpenes / pharmacology*
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Signal Transduction / drug effects
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Trans-Activators / antagonists & inhibitors*
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Vascular Cell Adhesion Molecule-1 / biosynthesis*
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Integrin alpha4beta1
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Integrins
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NF-kappa B
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Plant Extracts
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Proto-Oncogene Proteins
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Receptors, Lymphocyte Homing
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STAT6 Transcription Factor
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STAT6 protein, human
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Sesquiterpenes
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Stat6 protein, mouse
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Trans-Activators
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Vascular Cell Adhesion Molecule-1
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Interleukin-4
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parthenolide
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DNA
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Protein-Tyrosine Kinases
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JAK2 protein, human
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Jak2 protein, mouse
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Janus Kinase 2