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Human Ribonuclease A Superfamily Members, Eosinophil-Derived Neurotoxin and Pancreatic Ribonuclease, Induce Dendritic Cell Maturation and Activation¹

De Yang^*, Qian Chen, Helene F. Rosenberg^¶, Susanna M. Rybak, Dianne L. Newton, Zhao Yuan Wang^*, Qin Fu^||, Velizar T. Tchernev^||, Minjuan Wang^||, Barry Schweitzer^||, Stephen F. Kingsmore^||, Dhavalkumar D. Patel^||,#, Joost J. Oppenheim and O. M. Zack Howard^2,

^* Basic Research Program and Division of Cancer Treatment and Diagnosis/Developmental Therapeutics Program Support Program, Science Applications International Corporation (SAIC)-Frederick, Laboratory of Molecular Immunoregulation, Center for Cancer Research, and Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Frederick, MD 21702; ^¶ Eosinophil Pathophysiology Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; ^|| Molecular Staging, New Haven, CT 06511; and ^# Thurston Arthritis Research Center and Department of Medicine, University of North Carolina, Chapel Hill, NC 27599

A number of mammalian antimicrobial proteins produced by neutrophils and cells of epithelial origin have chemotactic and activating effects on host cells, including cells of the immune system. Eosinophil granules contain an antimicrobial protein known as eosinophil-derived neurotoxin (EDN), which belongs to the RNase A superfamily. EDN has antiviral and chemotactic activities in vitro. In this study, we show that EDN, and to a lesser extent human pancreatic RNase (hPR), another RNase A superfamily member, activates human dendritic cells (DCs), leading to the production of a variety of inflammatory cytokines, chemokines, growth factors, and soluble receptors. Human angiogenin, a RNase evolutionarily more distant to EDN and hPR, did not display such activating effects. Additionally, EDN and hPR also induced phenotypic and functional maturation DCs. These RNases were as efficacious as TNF-, but induced a different set of cytokine mediators. Furthermore, EDN production by human macrophages could be induced by proinflammatory stimuli. The results reveal the DC-activating activity of EDN and hPR and suggest that they are likely participants of inflammatory and immune responses. A number of endogenous mediators in addition to EDN have been reported to have both chemotactic and activating effects on APCs, and can thus amplify innate and Ag-specific immune responses to danger signals. We therefore propose these mediators be considered as endogenous multifunctional immune alarmins.

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