Arginine-rich cationic polypeptides amplify lipopolysaccharide-induced monocyte activation.
The human neutrophil-derived cationic protein CAP37, also known as azurocidin or heparin-binding protein, enhances the lipopolysaccharide (LPS)-induced release of tumor necrosis factor alpha (TNF-alpha) in isolated human monocytes. We measured the release of the proinflammatory cytokine interleukin-8 (IL-8) in human whole blood and found that in addition to CAP37, other arginine-rich cationic polypeptides, such as the small structurally related protamines, enhance LPS-induced monocyte activation. As CAP37 and protamines share high levels of arginine content, we tested different synthetic poly-L-amino acids and found that poly-L-arginine, and to a lesser extent poly-L-lysine, increased IL-8 production in LPS-stimulated human whole blood. Protamine-enhanced LPS responses remained unaffected by the presence of free L-arginine or L-lysine, indicating that basic polypeptides but not basic amino acids act synergistically with LPS. In agreement with observations previously reported for CAP37, the LPS-enhancing effect of poly-L-arginine was completely abolished upon antibody blockade of the human LPS receptor, CD14. Protamines, either immobilized or in solution, bound LPS specifically. Poly-L-arginines, protamines, and CAP37 were equally effective in inhibiting binding of LPS to immobilized L-arginines. Taken together, our results suggest a CD14-dependent mechanism by which arginine-rich cationic proteins modulate LPS-induced monocyte activation and support the prediction that other strongly basic proteins could act as amplifiers of LPS responses.
Bosshart
Herbert
H
Department of Surgery, University Hospital, 8091 Zurich, Switzerland.
Heinzelmann
Michael
M
D023181:Antimicrobial Cationic Peptides; D001120:Arginine / Q000737:chemistry; D001798:Blood Proteins / Q000737:chemistry / Q000494:pharmacology*; D002352:Carrier Proteins / Q000737:chemistry / Q000494:pharmacology*; D006493:Heparin / Q000378:metabolism; D006494:Heparin Antagonists / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D016209:Interleukin-8 / Q000097:blood*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology*; D008262:Macrophage Activation / Q000187:drug effects*; D009000:Monocytes; D011479:Protamines / Q000378:metabolism / Q000494:pharmacology
C062991:AZU1 protein, human; D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D002352:Carrier Proteins; D006494:Heparin Antagonists; D016209:Interleukin-8; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D011479:Protamines; D006493:Heparin; D001120:Arginine