title: Janex-1, a JAK3 inhibitor, ameliorates tumor necrosis factor-α-induced expression of cell adhesion molecules and improves myocardial vascular permeability in endotoxemic mice.
abstract: Vascular endothelial cells play an important role in leukocyte trafficking             during the inflammatory process. Proinflammatory cytokines activate the expression             of cell adhesion molecules in endothelial cells. Janus kinase (JAK) and signal             transducer and activator of transcription (STAT) are important intracellular cytokine             signaling molecules that are involved in immune responses. The purpose of this             study was to investigate the effect of JAK3 inhibition on the expression of tumor             necrosis factor (TNF)-α-induced cell adhesion molecules in vascular endothelial             cells and to evaluate the therapeutic potential of JAK3 for myocardial vascular             permeability in endotoxemic mice. A JAK3 inhibitor, JANEX-1, decreased the TNF-α-induced             expression of intercellular adhesion molecule (ICAM)-1, VCAM (vascular cell adhesion             molecule)-1 and fractalkine in human umbilical vein endothelial cells (HUVECs).             The downregulation of the expression of these cell adhesion molecules by JANEX-1             was mediated via suppression of STAT3 phosphorylation and nuclear factor-κB (NF-κB)             activation. In endotoxemic mice, pretreatment with JANEX-1 prevented not only             an increase in the cardiac ICAM-1 expression by LPS in the arteriolar and capillary             endothelial cells, but also myocardial vascular leakage. These results suggest             that inhibition of the JAK/STAT pathway by JANEX-1 ameliorates the expression             of TNF-α-induced cell adhesion molecules in HUVECs and improves myocardial vascular             permeability.
authors.affiliation: Department of Internal Medicine, Research Institute of Clinical                     Medicine and Diabetes Research Center, Chonbuk National University Medical                     School, Deokjin-gu, Jeonju-si 561-712, Republic of Korea.
authors.forename: Jung Eun
authors.initials: JE
authors.lastname: Lee
authors.forename: Ae Sin
authors.initials: AS
authors.lastname: Lee
authors.forename: Duk Hoon
authors.initials: DH
authors.lastname: Kim
authors.forename: Yu Jin
authors.initials: YJ
authors.lastname: Jung
authors.forename: Sik
authors.initials: S
authors.lastname: Lee
authors.forename: Byung-Hyun
authors.initials: BH
authors.lastname: Park
authors.forename: Sun Hwa
authors.initials: SH
authors.lastname: Lee
authors.forename: Sung Kwang
authors.initials: SK
authors.lastname: Park
authors.forename: Won
authors.initials: W
authors.lastname: Kim
authors.forename: Kyung Pyo
authors.initials: KP
authors.lastname: Kang
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D015815:Cell Adhesion Molecules / Q000276:immunology*; D054428:Chemokine CX3CL1 / Q000276:immunology; D003331:Coronary Vessels / Q000187:drug effects / Q000503:physiopathology; D019446:Endotoxemia / Q000188:drug therapy* / Q000503:physiopathology; D006321:Heart / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000276:immunology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology
chemical_list: D015815:Cell Adhesion Molecules; D054428:Chemokine CX3CL1; D011799:Quinazolines; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C116180:WHI P131; D018799:Intercellular Adhesion Molecule-1; D053616:Janus Kinase 3