title: Noncanonical Notch signaling modulates cytokine responses of dendritic cells to inflammatory stimuli.
abstract: Dendritic cell (DC)-derived cytokines play a key role in specifying adaptive immune responses tailored to the type of pathogen encountered and the local tissue environment. However, little is known about how DCs perceive the local environment. We investigated whether endogenous Notch signaling could affect DC responses to pathogenic stimuli. We demonstrate that concurrent Notch and TLR stimulation results in a unique cytokine profile in mouse bone-marrow derived DCs characterized by enhanced IL-10 and IL-2, and reduced IL-12 expression compared with TLR ligation alone. Unexpectedly, modulation of cytokine production occurred through a noncanonical Notch signaling pathway, independent of γ-secretase activity. Modulation required de novo protein synthesis, and PI3K, JNK, and ERK activity were necessary for enhanced IL-2 expression, whereas modulation of IL-10 required only PI3K activity. Further, we show that this γ-secretase-independent Notch pathway can induce PI3K activity. In contrast, expression of the canonical Notch target gene Hes1 was suppressed in DCs stimulated with Notch and TLR ligands simultaneously. Thus, our data suggest that Notch acts as an endogenous signal that modulates cytokine expression of DCs through a noncanonical pathway and therefore has the potential to tailor the subsequent adaptive immune response in a tissue- and/or stage-dependent manner.
authors: Division of Cell and Molecular Biology, Department of Life Sciences, Imperial College London, London SW7 2AZ, United Kingdom.
authors: Madeleine E
authors: ME
authors: Gentle
authors: Anna
authors: A
authors: Rose
authors: Laurence
authors: L
authors: Bugeon
authors: Margaret J
authors: MJ
authors: Dallman
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D002135:Calcium-Binding Proteins / Q000502:physiology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D008024:Ligands; D008070:Lipopolysaccharides / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D051881:Receptor, Notch1 / Q000378:metabolism / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000502:physiology; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D002135:Calcium-Binding Proteins; D016207:Cytokines; D018836:Inflammation Mediators; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D008070:Lipopolysaccharides; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D000072099:Serrate-Jagged Proteins