Human ribonuclease A superfamily members, eosinophil-derived neurotoxin and pancreatic ribonuclease, induce dendritic cell maturation and activation.
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-alpha, 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.
Yang
De
D
Basic Research Program, Science Applications International Corporation (SAIC)-Frederick, MD 21702, USA.
Chen
Qian
Q
Rosenberg
Helene F
HF
Rybak
Susanna M
SM
Newton
Dianne L
DL
Wang
Zhao Yuan
ZY
Fu
Qin
Q
Tchernev
Velizar T
VT
Wang
Minjuan
M
Schweitzer
Barry
B
Kingsmore
Stephen F
SF
Patel
Dhavalkumar D
DD
Oppenheim
Joost J
JJ
Howard
O M Zack
OM
D018952:Antigens, CD34 / Q000096:biosynthesis; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D004340:Drug Contamination; D004731:Endotoxins; D047208:Eosinophil-Derived Neurotoxin / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D016130:Immunophenotyping; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology; D009000:Monocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012259:Ribonuclease, Pancreatic / Q000502:physiology*; D013234:Stem Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D018952:Antigens, CD34; D004731:Endotoxins; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D047208:Eosinophil-Derived Neurotoxin; D012259:Ribonuclease, Pancreatic