title: Interleukin-6 receptor alpha blockade improves skin lesions in a murine model of systemic lupus erythematosus.
abstract: Systemic lupus erythematosus (SLE) is an autoimmune disease, characterized by antinuclear autoantibodies (ANA) and immunocomplexes, commonly affecting kidneys, skin, heart, lung or even the brain. We have shown that JunB(Δep) mice develop a SLE phenotype linked to increased epidermal Interleukin (IL)-6 secretion. Blocking of IL-6 receptor alpha (IL-6Rα) is considered as therapeutic strategy for the treatment of SLE. JunB(Δep) and wild-type mice were treated for short (5 weeks) or long term (21 weeks) with the IL-6Rα-blocking antibody MR16-1. Skin and kidney of mice were investigated by histology and immunofluorescence, and in addition, kidneys were analysed by electron microscopy. Furthermore, soluble IL-6R (sIL-6R), antihistone and antinucleosome antibodies levels were measured and associated with disease parameters. Treatment with MR16-1 resulted in significant improvement of SLE-like skin lesions in JunB(Δep) mice, compared to untreated mice. The sIL-6R amount upon long-term treatment with MR16-1 was significantly higher in JunB(Δep) versus untreated JunB(Δep) (P = 0.034) or wild-type mice (P = 0.034). MR16-1 treatment over these time spans did not significantly improve kidney pathology of immunoglobulin deposits causing impaired function. Significantly higher antihistone (P = 0.028) and antinucleosome antibody levels (P = 0.028) were measured in MR16-1-treated JunB(Δep) mice after treatment compared to levels before therapy. In conclusion, blockade of IL-6Rα improves skin lesions in a murine SLE model, but does not have a beneficial effect on autoimmune-mediated kidney pathology. Inhibition of IL-6R signalling might be helpful in lupus cases with predominant skin involvement, but combinatorial treatment might be required to restrain autoantibodies.
authors.affiliation: Department of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Birner
authors.affiliation: Department of Pathology, Medical University of Vienna, Vienna, Austria.|Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
authors.forename: Susanne
authors.initials: S
authors.lastname: Heider
authors.affiliation: Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Petzelbauer
authors.affiliation: Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Wolf
authors.affiliation: Department of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kornauth
authors.affiliation: Department of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Kuroll
authors.affiliation: Department of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Olaf
authors.initials: O
authors.lastname: Merkel
authors.affiliation: Division of Rheumatology, Department of Internal Medicine III, Osaka University, Suita City, Osaka, Japan.
authors.forename: Günter
authors.initials: G
authors.lastname: Steiner
authors.affiliation: Laboratory of Immune Regulation, Graduate School of Frontier Biosciences, Osaka University, Suita City, Osaka, Japan.
authors.forename: Tadamitsu
authors.initials: T
authors.lastname: Kishimoto
authors.affiliation: Institute of Biochemistry, University of Kiel, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: Labor Dr. Soleiman, Hall, Austria.
authors.forename: Afschin
authors.initials: A
authors.lastname: Soleiman
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria.|Medical University of Vienna, Vienna, Austria.
authors.forename: Richard
authors.initials: R
authors.lastname: Moriggl
authors.affiliation: Department of Pathology, Medical University of Vienna, Vienna, Austria.|Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Institute of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Lukas
authors.initials: L
authors.lastname: Kenner
mesh_terms: D000418:Albumins / Q000032:analysis; D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D001835:Body Weight; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D007074:Immunoglobulin G / Q000276:immunology; D007136:Immunoglobulins / Q000378:metabolism; D053698:Interleukin-6 Receptor alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism / Q000503:physiopathology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism / Q000473:pathology; D012871:Skin Diseases / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D000418:Albumins; D000974:Antibodies, Antinuclear; D007074:Immunoglobulin G; D007136:Immunoglobulins; D053698:Interleukin-6 Receptor alpha Subunit; C584097:JunB protein, mouse; D014157:Transcription Factors
keywords: SLE; interleukin 6; jun B