Chemoattraction of macrophages, T lymphocytes, and mast cells is evolutionarily conserved within the human alpha-defensin family.

Abstract

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.

• Authors: Jasmin Grigat, Afsaneh Soruri, Ulf Forssmann, Joachim Riggert, Jörg Zwirner
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 179 Issue 6 Pg. 3958-65 (Sep 15 2007) ISSN: 0022-1767 [Print] United States
• PMID: 17785833 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• alpha-Defensins
• Mitogen-Activated Protein Kinases

Topics

• Animals
• Cell Line
• Cell Line, Tumor
• Chemotaxis, Leukocyte (immunology)
• Conserved Sequence
• Dendritic Cells (cytology, immunology, metabolism)
• Evolution, Molecular
• Humans
• MAP Kinase Signaling System (immunology)
• Macrophages (cytology, immunology, metabolism)
• Mast Cells (cytology, immunology, metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, SCID
• Mitogen-Activated Protein Kinases (physiology)
• Multigene Family (immunology)
• T-Lymphocytes (cytology, immunology, metabolism)
• alpha-Defensins (chemistry, physiology)