IL-11 activates human endothelial cells to resist immune-mediated injury.
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.
Mahboubi
K
K
Molecular Cardiobiology Program, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
Biedermann
B C
BC
Carroll
J M
JM
Pober
J S
JS
D015703:Antigens, CD / Q000378:metabolism; D002478:Cells, Cultured; D003165:Complement System Proteins / Q000276:immunology; D050822:Cytokine Receptor gp130; D003602:Cytotoxicity, Immunologic; D004268:DNA-Binding Proteins / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D004730:Endothelium, Vascular / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000276:immunology* / Q000633:toxicity; D017370:Interleukin-11 / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D053703:Interleukin-11 Receptor alpha Subunit; D008562:Membrane Glycoproteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology; D010766:Phosphorylation; D018123:Receptors, Interleukin / Q000096:biosynthesis; D053702:Receptors, Interleukin-11; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D015534:Trans-Activators / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D014471:Umbilical Veins
D015703:Antigens, CD; D004268:DNA-Binding Proteins; C508428:IL11RA protein, human; C494199:IL6ST protein, human; D018836:Inflammation Mediators; D017370:Interleukin-11; D053703:Interleukin-11 Receptor alpha Subunit; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D018123:Receptors, Interleukin; D053702:Receptors, Interleukin-11; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D050822:Cytokine Receptor gp130; D014443:Tyrosine; D003165:Complement System Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases