title: High level monocyte chemoattractant protein-1 expression in transgenic mice increases their susceptibility to intracellular pathogens.
abstract: We have constructed transgenic mice in which the mouse mammary tumor virus long terminal repeat controls the expression of murine monocyte chemoattractant protein-1 (MCP-1). Several independently derived lines of transgenic mice constitutively expressed MCP-1 protein in a variety of organs. Protein extracts from these organs had substantial in vitro monocyte chemoattractant activity that was neutralized by an anti-MCP-1 Ab, indicating that transgenic MCP-1 protein is biologically active. However, no transgenic mouse at any age displayed monocyte infiltrates in MCP-1-expressing organs. Two transgenic lines had circulating MCP-1 levels of 13 to 26 ng/ml, which is a concentration sufficient to induce maximal monocyte chemotaxis in vitro. These transgenic lines showed a 1 to 1.5 log greater sensitivity to infection with Listeria monocytogenes and Mycobacterium tuberculosis. A third transgenic line had lower serum levels of MCP-1 and was resistant to L. monocytogenes. The results suggest that this transgenic model is one of monocyte nonresponsiveness to locally produced MCP-1 due to either receptor desensitization or neutralization of a chemoattractant gradient by high systemic concentrations of MCP-1. Regardless of the mechanism, the data indicate that constitutively high levels of MCP-1 expression do not induce monocytic infiltrates, and that MCP-1 is involved in the host response to intracellular pathogens.
authors.affiliation: Department of Medicine, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Rutledge
authors.forename: H
authors.initials: H
authors.lastname: Rayburn
authors.forename: R
authors.initials: R
authors.lastname: Rosenberg
authors.forename: R J
authors.initials: RJ
authors.lastname: North
authors.forename: R P
authors.initials: RP
authors.lastname: Gladue
authors.forename: C L
authors.initials: CL
authors.lastname: Corless
authors.forename: B J
authors.initials: BJ
authors.lastname: Rollins
mesh_terms: D000818:Animals; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D002633:Chemotaxis; D007108:Immune Tolerance; D008089:Listeria monocytogenes / Q000276:immunology* / Q000472:pathogenicity; D008088:Listeriosis / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000472:pathogenicity; D014376:Tuberculosis / Q000276:immunology* / Q000473:pathology
chemical_list: D018932:Chemokine CCL2