Chemoattraction of Macrophages, T Lymphocytes, and Mast Cells Is Evolutionarily Conserved within the Human α-Defensin Family

• Published in: Journal of Immunology Vol. 179; no. 6; pp. 3958 - 3965
• Main Authors: Grigat, Jasmin, Soruri, Afsaneh, Forssmann, Ulf, Riggert, Joachim, Zwirner, Jörg
• Format: Journal Article
• Language: English
• Published: United States 15.09.2007
• Subjects: alpha-Defensins - chemistry; alpha-Defensins - physiology; Animals; Cell Line; Cell Line, Tumor; Chemotaxis, Leukocyte - immunology; Conserved Sequence; Dendritic Cells - cytology; Dendritic Cells - immunology; Dendritic Cells - metabolism; Evolution, Molecular; Humans; Macrophages - cytology; Macrophages - immunology; Macrophages - metabolism; MAP Kinase Signaling System - immunology; Mast Cells - cytology; Mast Cells - immunology; Mast Cells - metabolism; Mice; Mice, Inbred BALB C; Mice, SCID; Mitogen-Activated Protein Kinases - physiology; Multigene Family - immunology; T-Lymphocytes - cytology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.179.6.3958

Human defensins are natural peptide antibiotics. On the basis of the position and bonding of six conserved cysteine residues, they are divided into two families, designated α- and β-defensins. Human α-defensins are expressed predominantly in neutrophils (human neutrophil peptides (HNP) 1–4) or intestinal Paneth cells (human defensins (HD) 5 and 6). Although α-defensins have been implicated in the pathogenesis of inflammatory bowel disease, their immunomodulatory functions are poorly understood. In the present study, HNP-1, HNP-3, and HD5 were found to be potent chemotaxins for macrophages but not dendritic cells using Gαi proteins and MAPK as signal transducers. α-Defensins were also chemoattractive for the human mast cell line HMC-1 but lacked, in contrast to β-defensins, the ability to induce intracellular calcium fluxes. Furthermore, HNP-1, HNP-3, and HD5 comparably mobilized naive as well as memory T lymphocytes. Using the protein kinase C (PKC) inhibitors GF109 and Gö6976, we observed a PKC-independent functional desensitization to occur between human α-defensins, which suggests a common receptor for HNP-1, HNP-3, and HD5 on immune cells. This α-defensin receptor was subject to heterologous desensitization by the PKC activator PMA and to PKC-dependent cross-desensitization by human β-defensins. Conversely, α-defensins desensitized β-defensin-mediated migration of immune cells in a PKC-dependent manner, suggesting unique receptors for both defensin families. Taken together, our observations indicate that chemoattraction of macrophages, T lymphocytes, and mast cells represents an immunomodulatory function which is evolutionarily conserved within the human α-defensin family and tightly regulated by β-defensins.