Chemoattraction of macrophages, T lymphocytes, and mast cells is evolutionarily conserved within the human alpha-defensin family.
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 alpha- and beta-defensins. Human alpha-defensins are expressed predominantly in neutrophils (human neutrophil peptides (HNP) 1-4) or intestinal Paneth cells (human defensins (HD) 5 and 6). Although alpha-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 Galphai proteins and MAPK as signal transducers. Alpha-defensins were also chemoattractive for the human mast cell line HMC-1 but lacked, in contrast to beta-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 alpha-defensins, which suggests a common receptor for HNP-1, HNP-3, and HD5 on immune cells. This alpha-defensin receptor was subject to heterologous desensitization by the PKC activator PMA and to PKC-dependent cross-desensitization by human beta-defensins. Conversely, alpha-defensins desensitized beta-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 alpha-defensin family and tightly regulated by beta-defensins.
Grigat
Jasmin
J
Department of Cellular and Molecular Immunology, Georg-August-University Göttingen, Göttingen, Germany.
Soruri
Afsaneh
A
Forssmann
Ulf
U
Riggert
Joachim
J
Zwirner
Jörg
J
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D017124:Conserved Sequence; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D019143:Evolution, Molecular; D006801:Humans; D020935:MAP Kinase Signaling System / Q000276:immunology; D008264:Macrophages / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D008407:Mast Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D005810:Multigene Family / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D023084:alpha-Defensins / Q000737:chemistry / Q000502:physiology*