CAP37, an antimicrobial protein of human neutrophil granules, is a specific chemoattractant for monocytes. Purified to homogeneity by sequential chromatography over carboxymethyl Sephadex, G-75 Sephadex, and hydrophobic interaction HPLC, demonstratively endotoxin-free CAP37 was maximally chemotactic over a range of 1.3 X 10-9-10-8 M. Thus it was active in the same molar concentrations as formyl-methionyl-leucyl-phenylalanine. CAP37 lacked chemotactic activity for neutrophils and lymphocytes. In checkerboard assays CAP37 had some chemokinetic activity as well. It was also chemotactic for rabbit mononuclear cells. Higher concentrations (2.7 X 10-8 M) were required for activity with rabbit cells than with human.

No abstract

Neutrophils are the innate immune system’s first line of defense. Neutrophils play a critical role in protecting the host against infectious pathogens, resolving sterile injuries, and mediating inflammatory responses. The granules of neutrophils and their constituent proteins are central to these functions. Although neutrophils may exert a protective role upon acute inflammatory conditions or insults, continued activity of neutrophils in chronic inflammatory diseases can contribute to tissue damage. Neutrophil granule proteins are involved in a number of chronic inflammatory conditions and diseases. However, the functions of these proteins in neuroinflammation and chronic neuroinflammatory diseases, including Alzheimer’s disease (AD), remain to be elucidated. In this review, we discuss recent findings from our lab and others that suggest possible functions for neutrophils and the neutrophil granule proteins, CAP37, neutrophil elastase, and cathepsin G, in neuroinflammation, with an emphasis on AD. These findings reveal that neutrophil granule proteins may exert both neuroprotective and neurotoxic effects. Further research should determine whether neutrophil granule proteins are valid targets for therapeutic interventions in chronic neuroinflammatory diseases.

We report the amino acid sequence of CAP37, a human neutrophil granule protein with antibacterial and monocyte‐specific chemotactic activity. CAP37 is a single‐chain protein consisting of 222 amino acid residues. It has three N‐glycosylation sites, at Asn residues 100, 114 and 145. Some species of CAP37 are glycosylated at all three sites; some at Asn‐114 alone, others at Asn‐114 and Asn‐110 or Asn‐145. CAP37 has 45% sequence identity to human neutrophil elastase, and 30–37% identity to several other granule serine proteinases. Despite these similarities, CAP37 is not a serine proteinase because the active site residues serine and histidine are replaced.

Cationic antimicrobial protein of M(r) 37 kDa (CAP37) is a multifunctional protein isolated from the granules of human neutrophils, which has important implications in host defense and inflammation. CAP37 was initially recognized for its strong antibiotic activity against Gram-negative bacteria and was viewed as a component of the oxygen-independent killing mechanism of the neutrophil. However, we now know that CAP37 has more far reaching and important functions. It is a physiological protein released during inflammation with a high potential of regulating monocyte/macrophage functions, such as chemotaxis, increased survival, and differentiation. Recently, it has been demonstrated that CAP37 binds endotoxin. It has the structure of a serine esterase but lacks enzymatic activity. The bactericidal and endotoxin binding domains of the molecule have been delineated. The identification of functional peptides should provide new insight into the mechanisms of endotoxin binding, antimicrobial activity, and chemotaxis and in the long term provide key insights into therapies for treating infections and endotoxic shock.

No abstract

Recent evidence suggests that inflammation in the central nervous system plays an important role in the pathogenesis of Alzheimer's disease. However, the identity of the inflammatory mediators, cytokines, and reactive oxygen species, that orchestrate cell death and plaque biogenesis in Alzheimer's disease, have yet to be elucidated. We have identified a novel inflammatory mediator, CAP37 (Cationic Antimicrobial Protein Mi 37 kDa), that promotes mononuclear cell chemotaxis, adhesion of monocytes to endothelium, and release of oxygen radicals from monocytes. In the present immunocytochemical study, we demonstrate the expression of CAP37 in the cerebral microvasculature in Alzheimer's disease. CAP37 was not detected in brain vessels of normal controls or patients with other neuropathologic conditions such as Pick's, Parkinson's, Binswanger's disease, Progressive Supranuclear Palsy, and Candida infection. Treatment of cerebral endothelial cultures with inflammatory mediators, cytokines or beta-amyloid results in the induction of CAP37 expression. These in vitro data showing endothelial-CAP37 expression after beta-amyloid treatment together with the previous demonstration that CAP37 stimulates mononuclear cell migration and activation, suggest that CAP37 could contribute to neuronal injury in Alzheimer's disease.

CAP37 modulated corneal epithelial cell proliferation and migration and upregulated adhesion molecules involved in leukocyte-epithelial and epithelial-extracellular matrix interactions.