title: The E3 ubiquitin ligase adaptor Ndfip1 regulates Th17 differentiation by limiting the production of proinflammatory cytokines.
abstract: Ndfip1 is an adaptor for the E3 ubiquitin ligase Itch. Both Ndfip1- and Itch-deficient T cells are biased toward Th2 cytokine production. In this study, we demonstrate that lungs from Ndfip1(-/-) mice showed increased numbers of neutrophils and Th17 cells. This was not because Ndfip1(-/-) T cells are biased toward Th17 differentiation. In fact, fewer Ndfip1(-/-) T cells differentiated into Th17 cells in vitro due to high IL-4 production. Rather, Th17 differentiation was increased in Ndfip1(-/-) mice due to increased numbers of IL-6-producing eosinophils. IL-6 levels in mice that lacked both Ndfip1 and IL-4 were similar to wild-type controls, and these mice had fewer Th17 cells in their lungs. These results indicate that Th2 inflammation, such as that observed in Ndfip1(-/-) mice, can increase Th17 differentiation by recruiting IL-6-producing eosinophils into secondary lymphoid organs and tissues. This may explain why Th17 cells develop within an ongoing Th2 inflammatory response.
authors.affiliation: School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Hilda E
authors.initials: HE
authors.lastname: Ramon
authors.forename: Allison M
authors.initials: AM
authors.lastname: Beal
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Liu
authors.forename: George Scott
authors.initials: GS
authors.lastname: Worthen
authors.forename: Paula M
authors.initials: PM
authors.lastname: Oliver
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation; D002465:Cell Movement / Q000276:immunology; D004804:Eosinophils / Q000276:immunology / Q000473:pathology; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins; D015847:Interleukin-4 / Q000096:biosynthesis / Q000276:immunology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction; D058408:Th1-Th2 Balance; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology*
chemical_list: D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D008565:Membrane Proteins; C499188:Ndfip1 protein, mouse; D015847:Interleukin-4; C471637:Itch protein, mouse; D044767:Ubiquitin-Protein Ligases