title: Interleukin-1 induces interleukin-8 secretion from endothelial cells by a juxtacrine mechanism.
abstract: Inflammation is characterized by migration of neutrophils through the endothelium, and the chemokine interleukin-8 (IL-8) appears to be involved. We asked whether adherence of cells bearing a membrane-form of interleukin 1 (IL-1) induces IL-8 secretion from human umbilical vein endothelial cells (HUVEC) and fibroblasts. Human peripheral blood mononuclear cells (PBMC) were stimulated with endotoxin for 12 hours and then fixed for 4 hours with paraformaldehyde. When these cells were added to HUVEC or fibroblasts, IL-8 production was induced. This stimulation by fixed PBMC was attributed to IL-1, because pretreatment of HUVEC or fibroblasts with IL-1 receptor antagonist (IL-1Ra) reduced the induction by 95% and 80%, respectively, P < .005. Using anti-IL-1 alpha monoclonal antibodies, reduction was complete, whereas anti-IL-1 beta had no effect. IL-1 alpha was shown on the surface of monocytes by fluorescence-activated cell sorter (FACS) analysis. Blockade of IL-1 receptors on PBMC did not affect the activity of membrane-associated IL-1 alpha, indicating that IL-1 is not anchored to the membrane through its receptors. However, PBMC treated with D-mannose before fixation resulted in a loss of activity; this loss of activity was associated with release of IL-1 alpha, not IL-1 beta, into the supernatant. Thus, anchoring of IL-1 alpha to the membrane may be via a lectin or mannose receptor-like interaction. Blockade of membrane IL-1 alpha required a 30-fold and fivefold excess of IL-1Ra compared with the amount required to block soluble IL-1 beta and IL-1 alpha, respectively. We conclude that the fixed PBMC IL-8 inducing activity is almost entirely caused by IL-1, that this represents IL-1 alpha bound to a surface lectin or mannose receptor on the monocyte, and that it functions in inflammation via juxtacrine interactions.
authors.affiliation: Department of Medicine, Tufts University, Boston, MA.
authors.forename: G
authors.initials: G
authors.lastname: Kaplanski
authors.forename: C
authors.initials: C
authors.lastname: Farnarier
authors.forename: S
authors.initials: S
authors.lastname: Kaplanski
authors.forename: R
authors.initials: R
authors.lastname: Porat
authors.forename: L
authors.initials: L
authors.lastname: Shapiro
authors.forename: P
authors.initials: P
authors.lastname: Bongrand
authors.forename: C A
authors.initials: CA
authors.lastname: Dinarello
mesh_terms: D002462:Cell Membrane / Q000378:metabolism; D002469:Cell Separation; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005404:Fixatives / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D007231:Infant, Newborn; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000494:pharmacology*; D016209:Interleukin-8 / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation; D008358:Mannose / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D012795:Sialoglycoproteins / Q000494:pharmacology; D012995:Solubility; D014471:Umbilical Veins
chemical_list: D017077:Culture Media, Conditioned; D005404:Fixatives; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D016209:Interleukin-8; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; D008358:Mannose