title: Eotaxin/CCL11 suppresses IL-8/CXCL8 secretion from human dermal microvascular endothelial cells.
abstract: The CC chemokine eotaxin/CCL11 is known to bind to the receptor CCR3 on eosinophils and Th2-type lymphocytes. In this study, we demonstrate that CCR3 is expressed on a subpopulation of primary human dermal microvascular endothelial cells and is up-regulated by TNF-alpha. We found that incubation of human dermal microvascular endothelial cells with recombinant eotaxin/CCL11 suppresses TNF-alpha-induced production of the neutrophil-specific chemokine IL-8/CXCL8. The eotaxin/CCL11-suppressive effect on endothelial cells was not seen on IL-1beta-induced IL-8/CXCL8 release. Eotaxin/CCL11 showed no effect on TNF-alpha-induced up-regulation of growth-related oncogene-alpha or IFN-gamma-inducible protein-10, two other CXC chemokines tested, and did not affect production of the CC chemokines monocyte chemoattractant protein-1/CCL2 and RANTES/CCL5, or the adhesion molecules ICAM-1 and E-selectin. These results suggest that eotaxin/CXCL11 is not effecting a general suppression of TNF-alphaR levels or signal transduction. Suppression of IL-8/CXCL8 was abrogated in the presence of anti-CCR3 mAb, pertussis toxin, and wortmannin, indicating it was mediated by the CCR3 receptor, G(i) proteins, and phosphatidylinositol 3-kinase signaling. Eotaxin/CCL11 decreased steady state levels of IL-8/CXCL8 mRNA in TNF-alpha-stimulated cells, an effect mediated in part by an acceleration of IL-8 mRNA decay. Eotaxin/CCL11 may down-regulate production of the neutrophil chemoattractant IL-8/CXCL8 by endothelial cells in vivo, acting as a negative regulator of neutrophil recruitment. This may play an important biological role in the prevention of overzealous inflammatory responses, aiding in the resolution of acute inflammation or transition from neutrophilic to mononuclear/eosinophilic inflammation.
authors.affiliation: Graduate Program in Cellular and Molecular Biology and Department of Pathology, University of Michigan Medical Center, Ann Arbor, MI 48109.
authors.forename: Sara S
authors.initials: SS
authors.lastname: Cheng
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Lukacs
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kunkel
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D054413:Chemokine CCL11; D018925:Chemokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019742:Chemokines, CC / Q000037:antagonists & inhibitors / Q000235:genetics / Q000494:pharmacology*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D008833:Microcirculation / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D037342:Pertussis Toxin; D020871:RNA Stability / Q000276:immunology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000276:immunology; D011994:Recombinant Proteins / Q000494:pharmacology; D012867:Skin / Q000098:blood supply / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015854:Up-Regulation / Q000276:immunology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D000911:Antibodies, Monoclonal; C515456:CCL11 protein, human; C515350:CCR3 protein, human; D015815:Cell Adhesion Molecules; D054413:Chemokine CCL11; D018925:Chemokines; D019742:Chemokines, CC; D016209:Interleukin-8; D012333:RNA, Messenger; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D010566:Virulence Factors, Bordetella; D037342:Pertussis Toxin; D000077191:Wortmannin