Abstract
IL-11, a gp130-signaling cytokine, is protective in several in vivo models of immune-mediated and inflammatory injury. HUVECs express IL-11 receptor alpha-chain and gp130. Human IL-11 causes rapid (2-10 min) tyrosine phosphorylation of gp130. IL-11 at 0.1 and 10 ng/ml induces tyrosine phosphorylation of STAT3 and STAT1, respectively, although maximal responses require 50 ng/ml. Phospho-STAT3 and phospho-STAT1 levels peak rapidly (2.5 min) and disappear by 60 min. The p42 and p44 mitogen-activated protein kinases (MAPKs) are phosphorylated in response to 0.3 ng/ml IL-11 with maximal activation at 30 ng/ml IL-11. Phosphorylation of p42 and p44 MAPKs, which can be prevented by a mitogen-activated protein/extracellular signal-related kinase kinase-1 inhibitor, peaks by 15-20 min and largely disappears by 40 min. IL-11 does not activate NF-kappaB nor does it inhibit NF-kappaB activation by TNF. Similarly, IL-11 neither induces E-selectin or ICAM-1 nor blocks induction by TNF. Although IL-11 does not alter class I MHC complex molecule expression, pretreatment with 0.5 ng/ml IL-11 partially protects HUVECs against lysis by allospecific class I MHC-restricted cytolytic T lymphocytes or by anti-class I MHC Ab plus heterologous C. IL-11-induced cytoprotection is protein synthesis dependent and may depend on mitogen-activated protein/extracellular signal-related kinase kinase-1. Our results indicate that low (i.e., STAT3- and MAPK-activating) concentrations of IL-11 confer resistance to immune-mediated injury in cultured HUVECs without inhibiting proinflammatory responses.
MeSH terms
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Antigens, CD / metabolism
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Cells, Cultured
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Complement System Proteins / immunology
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Cytokine Receptor gp130
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Cytotoxicity, Immunologic
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DNA-Binding Proteins / metabolism
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Dose-Response Relationship, Immunologic
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Endothelium, Vascular / enzymology
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Endothelium, Vascular / immunology*
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Endothelium, Vascular / metabolism
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Endothelium, Vascular / pathology*
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Enzyme Activation / immunology
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Humans
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Immunity, Innate
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Inflammation Mediators / immunology*
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Inflammation Mediators / toxicity
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Interleukin-11 / metabolism
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Interleukin-11 / pharmacology
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Interleukin-11 / physiology*
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Interleukin-11 Receptor alpha Subunit
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Membrane Glycoproteins / metabolism
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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 Kinases / metabolism
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NF-kappa B / physiology
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Phosphorylation
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Receptors, Interleukin / biosynthesis
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Receptors, Interleukin-11
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STAT1 Transcription Factor
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STAT3 Transcription Factor
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Signal Transduction / immunology
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T-Lymphocytes, Cytotoxic / immunology
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Trans-Activators / metabolism
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Tyrosine / metabolism
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Umbilical Veins
Substances
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Antigens, CD
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DNA-Binding Proteins
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IL11RA protein, human
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IL6ST protein, human
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Inflammation Mediators
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Interleukin-11
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Interleukin-11 Receptor alpha Subunit
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Membrane Glycoproteins
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NF-kappa B
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Receptors, Interleukin
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Receptors, Interleukin-11
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STAT1 Transcription Factor
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STAT1 protein, human
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STAT3 Transcription Factor
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STAT3 protein, human
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Trans-Activators
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Cytokine Receptor gp130
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Tyrosine
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Complement System Proteins
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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