title: IL-38 overexpression induces anti-inflammatory effects in mice arthritis models and in human macrophages in vitro.
abstract: OBJECTIVE
  Interleukin (IL)-38 is a newly characterised cytokine that belongs to the IL-1 family. This cytokine is expressed in the rheumatoid arthritis (RA) synovial tissue and IL-38 deficient mice have exacerbated arthritis. Here, we analysed the effect of IL-38 overexpression in the joints of arthritic mice, in human macrophages and synovial fibroblasts in vitro.
  
  
  METHODS
  Articular injections of an adeno-associated virus (AAV) 2/8 encoding IL-38 were performed in collagen-induced arthritis (CIA), K/BxN serum transfer-induced arthritis (STIA) and antigen-induced arthritis (AIA) in mice. The effect of IL-38 overexpression was evaluated through clinical scores, immunohistochemistry, microCT, Luminex and RT-qPCR analysis. THP-1 macrophages were transduced with a lentiviral vector to overexpress IL-38.
  
  
  RESULTS
  Clinical inflammatory scores were significantly decreased after AAV IL-38 injection in joints of mice with CIA and STIA, but not AIA. This decrease was accompanied by reduced macrophage infiltration and a decreased expression of Th17 cytokines (IL-17, IL-23, IL-22) and TNFα. However, IL-38 overexpression had no effect on cartilage or bone destruction. In vitro, the THP-1 monocytic cell line expressed less IL-6, TNFα and IL-23 after IL-38 overexpression. Conditioned media from these cells, containing released IL-38, also exert an anti-inflammatory effect on human primary macrophages and synovial fibroblasts from patients with RA.
  
  
  CONCLUSIONS
  This study shows for the first time that IL-38 overexpression attenuates the severity of experimental arthritis. IL-38 may exert its anti-inflammatory effects by decreasing the production of proinflammatory cytokines by macrophages and synovial fibroblasts. This effect can lead to the development of novel treatment strategies in arthritis.
authors.affiliation: INSERM, UMR 957, Equipe Labellisée LIGUE 2012, Nantes, France.|Université de Nantes, Nantes Atlantique Universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Faculté de Médecine, Nantes, France.
authors.forename: Marie-Astrid
authors.initials: MA
authors.lastname: Boutet
authors.affiliation: INSERM, UMR 957, Equipe Labellisée LIGUE 2012, Nantes, France.|Université de Nantes, Nantes Atlantique Universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Faculté de Médecine, Nantes, France.|Rheumatology Unit, Nantes University Hospital, Nantes, France.
authors.forename: Aurélie
authors.identifier: http://orcid.org/0000-0002-6008-503X
authors.initials: A
authors.lastname: Najm
authors.affiliation: INSERM, UMR 957, Equipe Labellisée LIGUE 2012, Nantes, France.|Université de Nantes, Nantes Atlantique Universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Faculté de Médecine, Nantes, France.|Rheumatology Unit, Nantes University Hospital, Nantes, France.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Bart
authors.affiliation: INSERM, UMR 957, Equipe Labellisée LIGUE 2012, Nantes, France.|Université de Nantes, Nantes Atlantique Universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Faculté de Médecine, Nantes, France.
authors.forename: Régis
authors.initials: R
authors.lastname: Brion
authors.affiliation: Rheumatology Unit, Nantes University Hospital, Nantes, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Touchais
authors.affiliation: INSERM, UMR 957, Equipe Labellisée LIGUE 2012, Nantes, France.|Université de Nantes, Nantes Atlantique Universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Faculté de Médecine, Nantes, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Trichet
authors.affiliation: INSERM, UMR 957, Equipe Labellisée LIGUE 2012, Nantes, France.|Université de Nantes, Nantes Atlantique Universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Faculté de Médecine, Nantes, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Layrolle
authors.affiliation: Department of Pathology and Immunology, University of Geneva School of Medicine, Geneva, Switzerland.|Division of Rheumatology, Department of Internal Medicine Specialties, University Hospitals of Geneva, Geneva, Switzerland.
authors.forename: Cem
authors.initials: C
authors.lastname: Gabay
authors.affiliation: Department of Pathology and Immunology, University of Geneva School of Medicine, Geneva, Switzerland.|Division of Rheumatology, Department of Internal Medicine Specialties, University Hospitals of Geneva, Geneva, Switzerland.
authors.forename: Gaby
authors.initials: G
authors.lastname: Palmer
authors.affiliation: INSERM, UMR 957, Equipe Labellisée LIGUE 2012, Nantes, France.|Université de Nantes, Nantes Atlantique Universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Faculté de Médecine, Nantes, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Blanchard
authors.affiliation: INSERM, UMR 957, Equipe Labellisée LIGUE 2012, Nantes, France.|Université de Nantes, Nantes Atlantique Universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Faculté de Médecine, Nantes, France.|Rheumatology Unit, Nantes University Hospital, Nantes, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Le Goff
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D015153:Blotting, Western; D001842:Bone and Bones / Q000000981:diagnostic imaging; D002358:Cartilage, Articular / Q000000981:diagnostic imaging; D002460:Cell Line; D017077:Culture Media, Conditioned; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology; D053759:Interleukin-23 / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D060888:Real-Time Polymerase Chain Reaction; D013583:Synovial Membrane / Q000166:cytology; D058504:Th17 Cells / Q000276:immunology; D059467:Transcriptome; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology; D055114:X-Ray Microtomography; D000097043:Interleukin-22
chemical_list: D017077:Culture Media, Conditioned; D020381:Interleukin-17; D053759:Interleukin-23; D015850:Interleukin-6; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D000097043:Interleukin-22; C571243:IL-38 protein, human
keywords: Arthritis; Cytokines; Inflammation