title: Recombinant IL-6 treatment protects mice from organ specific autoimmune disease by IL-6 classical signalling-dependent IL-1ra induction.
abstract: Cytokines are key regulators of physiological inflammatory responses, while aberrant cytokine expression contributes to pathogenesis of autoimmune diseases. We noted increased IL-6 levels in human and murine epidermolysis bullosa acquisita (EBA), a prototypic organ-specific autoimmune bullous dermatoses (AIBD) induced by autoantibodies to type VII collagen (COL7). In contrast to rheumatoid arthritis, blockade of IL-6 led to strikingly enhanced experimental EBA, while treatment with recombinant IL-6 was protective. This was due to classical IL-6 signalling and independent of IL-6 trans-signalling, as treatment of mice with sgp130Fc had no impact on EBA manifestation. Induction of EBA in mice led to increased IL-1ra levels in skin and serum, while blockade of IL-6 completely inhibited IL-1ra expression induced by autoantibodies to COL7. In line, treatment of mice with EBA with recombinant IL-6 induced IL-1ra concentrations exceeding those of untreated animals with EBA, and IL-1ra (anakinra) administration significantly impaired experimental EBA induction. We here identified a novel anti-inflammatory pathway in an organ-specific autoimmune disease. Modulation of this IL-1ra pathway by classical IL-6 signalling demonstrates anti-inflammatory and protective activities of IL-6 in vivo.
authors.affiliation: Excellence Cluster Inflammation at Interfaces, Schleswig-Holstein, Germany; Department of Dermatology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany. unni.samavedam@uksh.de
authors.forename: Unni Krishna S R L
authors.initials: UK
authors.lastname: Samavedam
authors.forename: Kathrin
authors.initials: K
authors.lastname: Kalies
authors.forename: Jürgen
authors.initials: J
authors.lastname: Scheller
authors.forename: Hengameh
authors.initials: H
authors.lastname: Sadeghi
authors.forename: Yask
authors.initials: Y
authors.lastname: Gupta
authors.forename: Marcel F
authors.initials: MF
authors.lastname: Jonkman
authors.forename: Enno
authors.initials: E
authors.lastname: Schmidt
authors.forename: Jürgen
authors.initials: J
authors.lastname: Westermann
authors.forename: Detlef
authors.initials: D
authors.lastname: Zillikens
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.forename: Ralf J
authors.initials: RJ
authors.lastname: Ludwig
mesh_terms: D000818:Animals; D017209:Apoptosis; D001323:Autoantibodies / Q000276:immunology; D001327:Autoimmune Diseases / Q000097:blood / Q000517:prevention & control*; D024143:Collagen Type VII / Q000276:immunology; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D016107:Epidermolysis Bullosa Acquisita / Q000097:blood / Q000276:immunology / Q000517:prevention & control*; D006801:Humans; D007249:Inflammation; D053590:Interleukin 1 Receptor Antagonist Protein / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology; D012867:Skin / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000276:immunology; D000093242:Interleukin-6 Inhibitors
chemical_list: D001323:Autoantibodies; D024143:Collagen Type VII; D016207:Cytokines; D053590:Interleukin 1 Receptor Antagonist Protein; D015850:Interleukin-6; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D000093242:Interleukin-6 Inhibitors; C560825:Timp1 protein, mouse; C519852:olamkicept