title: Survival and migration of human dendritic cells are regulated by an IFN-alpha-inducible Axl/Gas6 pathway.
abstract: Axl, a prototypic member of the transmembrane tyrosine kinase receptor family, is known to regulate innate immunity. In this study, we show that Axl expression is induced by IFN-alpha during human dendritic cell (DC) differentiation from monocytes (IFN/DC) and that constitutively Axl-negative, IL-4-differentiated DC (IL-4/DC) can be induced to up-regulate Axl by IFN-alpha. This effect is inhibited by TLR-dependent maturation stimuli such as LPS, poly(I:C), TLR7/8 ligand, and CD40L. LPS-induced Axl down-regulation on the surface of human IFN-alpha-treated DC correlates with an increased proteolytic cleavage of Axl and with elevated levels of its soluble form. GM6001 and TAPI-1, general inhibitors of MMP and ADAM family proteases, restored Axl expression on the DC surface and diminished Axl shedding. Furthermore, stimulation of Axl by its ligand, Gas6, induced chemotaxis of human DC and rescued them from growth factor deprivation-induced apoptosis. Our study provides the first evidence that Gas6/Axl-mediated signaling regulates human DC activities, and identifies Gas6/Axl as a new DC chemotaxis pathway. This encourages one to explore whether dysregulation of this novel pathway in human DC biology is involved in autoimmunity characterized by high levels of IFN-alpha.
authors: Department of Public Health and Microbiology, University of Torino, Torino, Italy.
authors: Sara
authors: S
authors: Scutera
authors: Tiziana
authors: T
authors: Fraone
authors: Tiziana
authors: T
authors: Musso
authors: Paola
authors: P
authors: Cappello
authors: Silvia
authors: S
authors: Rossi
authors: Daniele
authors: D
authors: Pierobon
authors: Zane
authors: Z
authors: Orinska
authors: Ralf
authors: R
authors: Paus
authors: Silvia
authors: S
authors: Bulfone-Paus
authors: Mirella
authors: M
authors: Giovarelli
mesh_terms: D002454:Cell Differentiation / Q000276:immunology; D002465:Cell Movement / Q000276:immunology*; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000502:physiology*; D016898:Interferon-alpha / Q000502:physiology*; D015847:Interleukin-4 / Q000502:physiology; D008070:Lipopolysaccharides / Q000502:physiology; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D016898:Interferon-alpha; D015847:Interleukin-4; D008070:Lipopolysaccharides; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C000722289:AXL protein, human