title: IL-6 Trans-Signaling Drives Murine Crescentic GN.
abstract: The role of IL-6 signaling in renal diseases remains controversial, with data describing both anti-inflammatory and proinflammatory effects. IL-6 can act via classic signaling, engaging its two membrane receptors gp130 and IL-6 receptor (IL-6R). Alternatively, IL-6 trans-signaling requires soluble IL-6R (sIL-6R) to act on IL-6R-negative cells that express gp130. Here, we characterize the role of both pathways in crescentic nephritis. Patients with crescentic nephritis had significantly elevated levels of IL-6 in both serum and urine. Similarly, nephrotoxic serum-induced nephritis (NTN) in BALB/c mice was associated with elevated serum IL-6 levels. Levels of serum sIL-6R and renal downstream signals of IL-6 (phosphorylated signal transducer and activator of transcription 3, suppressor of cytokine signaling 3) increased over time in this model. Simultaneous inhibition of both IL-6 signaling pathways using anti-IL-6 antibody did not have a significant impact on NTN severity. In contrast, specific inhibition of trans-signaling using recombinant sgp130Fc resulted in milder disease. Vice versa, specific activation of trans-signaling using a recombinant IL-6-sIL-6R fusion molecule (Hyper-IL-6) significantly aggravated NTN and led to increased systolic BP in NTN mice. This correlated with increased renal mRNA synthesis of the Th17 cell cytokine IL-17A and decreased synthesis of resistin-like alpha (RELMalpha)-encoding mRNA, a surrogate marker of lesion-mitigating M2 macrophage subtypes. Collectively, our data suggest a central role for IL-6 trans-signaling in crescentic nephritis and offer options for more effective and specific therapeutic interventions in the IL-6 system.
authors.affiliation: Division of Nephrology and Immunology, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen Germany; Institute of Biochemistry and Molecular Biology, RWTH Aachen University, Aachen, Germany; gbraun@ukaachen.de.
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Braun
authors.affiliation: Division of Nephrology and Immunology, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen Germany; Division of Nephrology, Showa University Fujigaoka Hospital, Yokohama, Japan;
authors.forename: Yoshikuni
authors.initials: Y
authors.lastname: Nagayama
authors.affiliation: Division of Nephrology and Immunology, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen Germany; Division of Nephrology, Showa University Fujigaoka Hospital, Yokohama, Japan;
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Maruta
authors.affiliation: Division of Gastroenterology, Metabolic Diseases and Intensive Care, RWTH Aachen University, Aachen, Germany;
authors.forename: Felix
authors.initials: F
authors.lastname: Heymann
authors.affiliation: Division of Nephrology and Immunology, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen Germany;
authors.forename: Claudia R
authors.initials: CR
authors.lastname: van Roeyen
authors.affiliation: Division of Nephrology and Immunology, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen Germany; Institute of Pathology, RWTH Aachen University, Aachen, Germany;
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Klinkhammer
authors.affiliation: Division of Nephrology and Immunology, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen Germany; Institute of Pathology, RWTH Aachen University, Aachen, Germany; Institute of Molecular Biomedicine, Comenius University, Bratislava, Slovakia;
authors.forename: Peter
authors.initials: P
authors.lastname: Boor
authors.affiliation: Division of Nephrology and Immunology, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen Germany;
authors.forename: Luigi
authors.initials: L
authors.lastname: Villa
authors.affiliation: Department of Medicine, Section of Nephrology, Boston University School of Medicine, Boston, MA; and.
authors.forename: David J
authors.initials: DJ
authors.lastname: Salant
authors.affiliation: Division of Nephrology and Immunology, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen Germany;
authors.forename: Ute
authors.initials: U
authors.lastname: Raffetseder
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: Division of Nephrology and Immunology, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen Germany;
authors.forename: Tammo
authors.initials: T
authors.lastname: Ostendorf
authors.affiliation: Division of Nephrology and Immunology, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen Germany;
authors.forename: Jürgen
authors.initials: J
authors.lastname: Floege
mesh_terms: D000818:Animals; D005921:Glomerulonephritis / Q000209:etiology*; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015398:Signal Transduction
chemical_list: D015850:Interleukin-6
keywords: albuminuria; glomerular disease; nephritis; proteinuria