Potential role of monocyte chemoattractant protein 1/JE in monocyte/macrophage-dependent IgA immune complex alveolitis in the rat

M. L. Jones, M. S. Mulligan, C. M. Flory, P. A. Ward, J. S. Warren

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We have examined the role of monocyte chemoattractant protein 1 (MCP 1) in the pathogenesis of monocyte/macrophage-dependent IgA immune complex alveolitis in the rat. Rat MCP 1 was cloned and expressed in order to facilitate analysis of its function in rat models of human disease. A cDNA library was constructed from rat pulmonary artery endothelial cells stimulated with TNF-α. The cDNA library was screened with synthetic oligonucleotide probes based on the recently published rat MCP 1 cDNA sequence. Among numerous MCP 1-positive clones, four full length (approximately 480 bp) cDNA were rescued, amplified by polymerase chain reaction, and ligated into a pJVETLZ baculovirus transfer vector. Spodoptera frugiperda insect cells (Sf-21) infected with baculovirus recombinants (Autographa californica nuclear polyhedrosis virus) bearing properly oriented MCP 1 cDNA (AcMCP 1) directed the expression of unique peptides of 18, 21, and 23 kDa. Treatment of AcMCP 1-infected Sf-21 cells with tunicamycin resulted in reduced production of the 21- and 23-kDa proteins and an increase in 16- to 18-kDa products, the predicted size range of uncleaved and nonglycosylated rat MCP 1. Denatured and refolded 23-kDa and 21-kDa rat MCP 1 species exhibited dose-dependent monocyte-specific chemotactic activity at concentrations as low as 10-10 M whereas the 18-kDa species exhibited negligible activity. Antibodies that react with the 18-kDa, 21-kDa, and 23-kDa MCP 1 bands by Western immunoblot, block rat rMCP 1-directed monocyte chemotaxis, and neutralize monocyte-specific chemotactic activity secreted by TNF-stimulated rat endothelial cells were raised in rabbits immunized with the 23-kDa MCP 1 species. Intravenous administration of anti-MCP 1 antibodies upon initiation of IgA immune complex lung injury resulted in a marked reduction in lung injury as measured by pulmonary vascular permeability, alveolar hemorrhage, and pulmonary monocyte/macrophage recruitment. These data suggest that MCP 1 may play an important role in the pathogenesis of monocyte/ macrophage-dependent IgA immune complex alveolitis in the rat.

Original languageEnglish (US)
Pages (from-to)2147-2154
Number of pages8
JournalJournal of Immunology
Issue number6
StatePublished - Sep 15 1992
Externally publishedYes


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