title: Transgenic mice expressing different levels of soluble platelet/endothelial cell adhesion molecule-IgG display distinct inflammatory phenotypes.
abstract: Platelet/endothelial cell adhesion molecule-1 (PECAM-1, CD31), expressed on the surfaces of leukocytes and concentrated in the junctions between endothelial cells plays an important role in transendothelial migration of neutrophils and monocytes. Soluble recombinant PECAM-IgG injected i.v. into mice blocks acute leukocyte emigration by 80%. To study the role of PECAM in models of chronic inflammation, we generated transgenic mice constitutively expressing soluble full-length murine PECAM as an IgG chimera. Three founder lines expressed this transgene and constitutively secreted murine PECAM-IgG into the plasma where it was maintained at characteristic concentrations for each line. All mice had similar hematologic profiles to wild-type littermates and were healthy when maintained in the standard laboratory animal facility. Both the leukocytes and the endothelium of mice of all transgenic lines expressed the same levels of endogenous PECAM-1 as wild-type littermates. Similarly, there were no detectable differences in the expression of several other common leukocyte and endothelial cell adhesion molecules. Mice that produced moderate (10-20 microg/ml) concentrations of PECAM-IgG demonstrated a severely blunted acute inflammatory response, despite mobilizing appropriate numbers of circulating leukocytes. Surprisingly, mice that constitutively produced high (400-1,000 microg/ml) concentrations of PECAM-IgG were unresponsive to its anti-inflammatory effects. This is the first demonstration that a soluble form of a cell adhesion molecule can be stably expressed and retain efficacy in vivo over prolonged periods. This approach is applicable to many other extracellular molecules. However, the plasma concentrations of such constitutively produced inhibitors may greatly influence the resulting phenotype.
authors.affiliation: Department of Pathology and Division of Vascular Biology, Weill Medical College of Cornell University, New York 10021, USA.
authors.forename: F
authors.initials: F
authors.lastname: Liao
authors.forename: A R
authors.initials: AR
authors.lastname: Schenkel
authors.forename: W A
authors.initials: WA
authors.lastname: Muller
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002908:Chronic Disease; D003433:Crosses, Genetic; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics*; D007274:Injections, Intraperitoneal; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D010538:Peritonitis / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D010641:Phenotype; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000097:blood / Q000235:genetics; D012995:Solubility; D013864:Thioglycolates / Q000008:administration & dosage
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007074:Immunoglobulin G; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011993:Recombinant Fusion Proteins; D013864:Thioglycolates