title: Effects of an interleukin-15 antagonist on systemic and skeletal alterations in mice with DSS-induced colitis.
abstract: Inflammatory bowel diseases are commonly complicated by weight and bone loss. We hypothesized that IL-15, a pro-inflammatory cytokine expressed in colitis and an osteoclastogenic factor, could play a central role in systemic and skeletal complications of inflammatory bowel diseases. We evaluated the effects of an IL-15 antagonist, CRB-15, in mice with chronic colitis induced by oral 2% dextran sulfate sodium for 1 week, followed by another 1% for 2 weeks. During the last 2 weeks, mice were treated daily with CRB-15 or an IgG2a control antibody. Intestinal inflammation, disease severity, and bone parameters were evaluated at days 14 and 21. CRB-15 improved survival, early weight loss, and colitis clinical score, although colon damage and inflammation were prevented in only half the survivors. CRB-15 also delayed loss of femur bone mineral density and trabecular microarchitecture. Bone loss was characterized by decreased bone formation, but increased bone marrow osteoclast progenitors and osteoclast numbers on bone surfaces. CRB-15 prevented the suppression of osteoblastic markers of bone formation, and reduced osteoclast progenitors at day 14, but not later. However, by day 21, CRB-15 decreased tumor necrosis factor α and increased IL-10 expression in bone, paralleling a reduction of osteoclasts. These results delineate the role of IL-15 on the systemic and skeletal manifestations of chronic colitis and provide a proof-of-concept for future therapeutic developments.
authors.affiliation: Service of Bone Diseases, Department of Medical Specialties, Geneva University Hospital and Faculty of Medicine, Geneva, Switzerland.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Brounais-Le Royer
authors.forename: Dominique D
authors.initials: DD
authors.lastname: Pierroz
authors.forename: Dominique
authors.initials: D
authors.lastname: Velin
authors.forename: Christophe
authors.initials: C
authors.lastname: Frossard
authors.forename: Xin Xiao
authors.initials: XX
authors.lastname: Zheng
authors.forename: Hans-Anton
authors.initials: HA
authors.lastname: Lehr
authors.forename: Sylvie
authors.initials: S
authors.lastname: Ferrari-Lacraz
authors.forename: Serge L
authors.initials: SL
authors.lastname: Ferrari
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D001853:Bone Marrow / Q000378:metabolism; D002908:Chronic Disease; D003092:Colitis / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology / Q000517:prevention & control*; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D005269:Femur / Q000473:pathology / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D019409:Interleukin-15 / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000187:drug effects / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D010024:Osteoporosis / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D012720:Severity of Illness Index; D016019:Survival Analysis
chemical_list: D016207:Cytokines; C440611:IL-15-Fcgamma2a protein, human; D018836:Inflammation Mediators; D019409:Interleukin-15; D011993:Recombinant Fusion Proteins; D016264:Dextran Sulfate