Arginine-Rich Cationic Polypeptides Amplify Lipopolysaccharide-Induced Monocyte Activation

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Abstract
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-α) 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.