Abstract
T1/ST2 is a member of the interleukin (IL)-1 receptor superfamily, possessing three immunoglobulin domains extracellularly and a Toll/IL1R (TIR) domain intracellularly. The ligand for T1/ST2 is not known. T1/ST2 is expressed on Type 2 T helper (Th2) cells, and its role appears to be in the regulation of Th2 cell function. Here, we have investigated T1/ST2 signal transduction, using either transient overexpression of T1/ST2 or a cross-linking monoclonal antibody to activate cells. We demonstrate that T1/ST2 does not activate the transcription factor NF-kappaB when overexpressed in murine thymoma EL4 cells, or in the mast cell line P815 treated with the anti-T1/ST2 antibody. However, a chimera comprising the extracellular domain of the type 1 IL-1 receptor and the intracellular domain of T1/ST2 activates NF-kappaB both by overexpression and in response to IL-1. This artificial activation requires the IL1RAcP recruited via the extracellular portion (IL1R1) of the chimera. T1/ST2 is, however, able to activate the transcription factor activator protein-1 (AP-1), increase phosphorylation of c-Jun, and activate the MAP kinases c-Jun N-terminal kinase (JNK), p42/p44 and p38. Anti-T1/ST2 also induces the selective expression of IL-4 but not IFN-gamma in naive T cells. Importantly, this effect is blocked by prior treatment with the JNK inhibitor SP600125 confirming that JNK as a key effector in T1/ST2 signaling. The lack of effect on NF-kappaB when T1/ST2 is homodimerized identifies T1/ST2 as the first member of the IL-1 receptor superfamily so far studied that is apparently unable to activate NF-kappaB, consistent with evidence indicating the lack of a role for NF-kappaB in Th2 cell function.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Antigens, Differentiation / metabolism
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CD4-Positive T-Lymphocytes / metabolism
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Cell Line
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Cell Nucleus / metabolism
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Cross-Linking Reagents / pharmacology
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Cytokines / metabolism
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Dimerization
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Dose-Response Relationship, Drug
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Enzyme Activation
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Female
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Flow Cytometry
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Genes, Reporter
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Genetic Vectors
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Humans
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Immunoblotting
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Interferon-gamma / metabolism
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Interleukin-1 Receptor-Like 1 Protein
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Interleukin-4 / metabolism*
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JNK Mitogen-Activated Protein Kinases
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Ligands
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Luciferases / metabolism
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MAP Kinase Kinase 4
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Membrane Proteins / chemistry*
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Membrane Proteins / metabolism*
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Mice
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Mice, Inbred BALB C
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinase Kinases / metabolism*
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Mitogen-Activated Protein Kinases / metabolism
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Myeloid Differentiation Factor 88
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NF-kappa B / metabolism
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Precipitin Tests
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Protein Binding
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Protein Structure, Tertiary
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Receptors, Cell Surface
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Receptors, Immunologic / metabolism
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Receptors, Interleukin
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Receptors, Interleukin-1 / chemistry
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Receptors, Interleukin-1 / metabolism*
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Signal Transduction*
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Th2 Cells / metabolism
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Transfection
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Tumor Cells, Cultured
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p38 Mitogen-Activated Protein Kinases
Substances
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Adaptor Proteins, Signal Transducing
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Antigens, Differentiation
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Cross-Linking Reagents
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Cytokines
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IL1RL1 protein, human
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Il1rl1 protein, mouse
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Interleukin-1 Receptor-Like 1 Protein
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Ligands
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MYD88 protein, human
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Membrane Proteins
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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NF-kappa B
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Receptors, Cell Surface
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Receptors, Immunologic
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Receptors, Interleukin
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Receptors, Interleukin-1
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Interleukin-4
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Interferon-gamma
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Luciferases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 4
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Mitogen-Activated Protein Kinase Kinases