title: Coengagement of ICAM-3 and Fc receptors induces chemokine secretion and spreading by myeloid leukocytes.
abstract: ICAM-3 is expressed at high levels on myeloid leukocytes, but its function on these cells is unknown. We tested the hypothesis that it transduces outside-in proinflammatory signals using immobilized mAbs to engage ICAM-3 on freshly isolated human monocytes and neutrophils. Two immobilized Abs that recognize epitopes in the extracellular domain 1 of ICAM-3, which is critical for recognition by the alphaL/beta2 integrin, potently induced secretion of MIP-1alpha, IL-8, and MCP-1 by monocytes and triggered IL-8 secretion by neutrophils. These chemokines are products of immediate-early genes that are induced when myeloid cells are activated. Chemokine secretion induced by "triggering" Abs was greater than that induced by isotype-matched immobilized Abs against ICAM-1, ICAM-2, PECAM-1, control Igs, or immobilized control proteins. Coengagement of ICAM-3 and Fc receptors (FcgammaRI or FcgammaRII) was required for maximal chemokine secretion by monocytes. Microscopy documented that there is also dramatic spreading of monocytes when surface ICAM-3 is engaged by immobilized Abs. Spreading was induced by Fab and F(ab')2 fragments of triggering anti-ICAM-3 mAb, demonstrating direct outside-in signaling, but was not required for chemokine secretion. These experiments indicate that ICAM-3 may transmit outside-in signals when it is engaged by beta2 integrins during myeloid cell-cell interactions in inflammatory lesions. Binding of Fc receptors by Ig in the local environment can amplify the responses.
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, Salt Lake City, UT 84112, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Kessel
authors.forename: J
authors.initials: J
authors.lastname: Hayflick
authors.forename: A S
authors.initials: AS
authors.lastname: Weyrich
authors.forename: P A
authors.initials: PA
authors.lastname: Hoffman
authors.forename: M
authors.initials: M
authors.lastname: Gallatin
authors.forename: T M
authors.initials: TM
authors.lastname: McIntyre
authors.forename: S M
authors.initials: SM
authors.lastname: Prescott
authors.forename: G A
authors.initials: GA
authors.lastname: Zimmerman
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD; D000943:Antigens, Differentiation; D015815:Cell Adhesion Molecules / Q000276:immunology / Q000378:metabolism*; D002465:Cell Movement / Q000276:immunology*; D018925:Chemokines / Q000378:metabolism*; D006801:Humans; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism*; D011961:Receptors, Fc / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D015815:Cell Adhesion Molecules; D018925:Chemokines; C483616:ICAM3 protein, human; D011961:Receptors, Fc