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Papers In Press, published online ahead of print April 12, 2004
Dept. of Medicine, Washington University School of Medicine, Saint Louis, MO 63110
Corresponding Author: azzaq{at}im.wustl.edu
Surfactant protein D (SP-D) plays important roles in innate immunity including the defense against bacteria, fungi, and respiratory viruses. Because SP-D specifically interacts with neutrophils that infiltrate the lung in response to acute inflammation and infection, we examined the hypothesis that the neutrophil-derived serine proteinases (NSPs): neutrophil elastase (NE), proteinase-3 (PR3), and cathepsin G (CG) degrade SP-D. All three human NSPs specifically cleaved recombinant rat and natural human SP-D dodecamers in a time- and dose-dependent manner, which was reciprocally dependent on the calcium concentration. The NSPs generated similar, relatively stable, disulfide-crosslinked immunoreactive fragments of ~35 kDa (reduced), and sequencing of a major catheptic fragment definitively localized the major sites of cleavage to a highly conserved sub-region of the carbohydrate recognition domain (CRD). Cleavage markedly reduced the ability of SP-D to promote bacterial aggregation and to bind to yeast mannan in vitro. Incubation of SP-D with isolated murine neutrophils led to the generation of similar fragments, and cleavage was inhibited with synthetic and natural serine proteinase inhibitors. In addition, neutrophils genetically deficient in NE and/or CG were impaired in their ability to degrade SP-D. Using a mouse model of acute bacterial pneumonia, we observed the accumulation of SP-D at sites of neutrophil infiltration coinciding with the appearance of ~35 kDa SP-D fragments in bronchoalveolar lavage fluids. Together, our data suggest that neutrophil-derived serine proteinases cleave SP-D at sites of inflammation with potential deleterious effects on its biological functions.
J. Biol. Chem, 10.1074/jbc.M402936200
Submitted on March 16, 2004
Revised on April 9, 2004
Accepted on April 12, 2004
Neutrophil serine proteinases inactivate surfactant protein D by cleaving within a conserved Sub-region of the carbohydrate recognition domain
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