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Chemoattraction of Macrophages, T Lymphocytes, and Mast Cells Is Evolutionarily Conserved within the Human -Defensin Family¹

Jasmin Grigat^2,*, Afsaneh Soruri^2,*, Ulf Forssmann^3,,, Joachim Riggert and Jörg Zwirner^4,*

^* Department of Cellular and Molecular Immunology and Transfusion Medicine, Georg-August-University Göttingen, Göttingen, Germany; and IPF PharmaCeuticals and Center of Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany

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 - and -defensins. Human -defensins are expressed predominantly in neutrophils (human neutrophil peptides (HNP) 1–4) or intestinal Paneth cells (human defensins (HD) 5 and 6). Although -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 G_i proteins and MAPK as signal transducers. -Defensins were also chemoattractive for the human mast cell line HMC-1 but lacked, in contrast to -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 -defensins, which suggests a common receptor for HNP-1, HNP-3, and HD5 on immune cells. This -defensin receptor was subject to heterologous desensitization by the PKC activator PMA and to PKC-dependent cross-desensitization by human -defensins. Conversely, -defensins desensitized -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 -defensin family and tightly regulated by -defensins.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant from the Deutsche Forschungsgemeinschaft to A.S. (SO 478/1).

² J.G. and A.S. contributed equally.

³ Current address: Merck KGaA, Darmstadt, Germany.

⁴ Address correspondence and reprint requests to Dr. Jörg Zwirner, Department of Cellular and Molecular Immunology, Georg-August-University Göttingen, Humboldtallee 34, Göttingen, Germany. E-mail address: jzwirne{at}gwdg.de

⁵ Abbreviations used in this paper: HNP, human neutrophil protein; HD, human defensin; DC, dendritic cell; PKC, protein kinase C; HBD, human -defensin.