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Published on: March 10, 2015
Effects of an interleukin-15 antagonist on systemic and skeletal alterations in mice with DSS-induced colitis
Bénédicte Brounais-Le Royer1, Dominique D Pierroz, Dominique Velin
1Service of Bone Diseases, Department of Medical Specialties, Geneva University Hospital and Faculty of Medicine, Geneva, Switzerland.
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.
Insights
Interleukin-15 (IL-15) drives weight and bone loss in inflammatory bowel diseases. An IL-15 antagonist, CRB-15, improved survival and bone density in colitis models, suggesting therapeutic potential.
Area of Science:
- Immunology
- Gastroenterology
- Bone Biology
Background:
- Inflammatory bowel diseases (IBD) are associated with significant weight loss and bone density reduction.
- The pro-inflammatory cytokine Interleukin-15 (IL-15) is implicated in colitis and bone resorption.
- IL-15's role in systemic and skeletal complications of IBD requires further elucidation.
Purpose of the Study:
- To investigate the role of IL-15 in the systemic and skeletal complications of chronic colitis.
- To evaluate the therapeutic efficacy of an IL-15 antagonist (CRB-15) in a murine model of colitis.
Main Methods:
- Chronic colitis was induced in mice using dextran sulfate sodium (DSS).
- Mice were treated with either CRB-15 or a control antibody during the colitis induction.
- Evaluated outcomes included survival, weight, clinical disease scores, intestinal inflammation, and bone parameters (bone mineral density, microarchitecture, bone formation, and resorption markers).
Main Results:
- CRB-15 treatment improved survival, mitigated early weight loss, and reduced clinical colitis scores.
- While CRB-15 did not fully prevent colon damage, it delayed bone loss, preserving femur bone mineral density and trabecular microarchitecture.
- CRB-15 prevented the suppression of bone formation markers and reduced osteoclast progenitors early on, later decreasing pro-inflammatory cytokines and osteoclast numbers in bone.
Conclusions:
- IL-15 plays a critical role in the systemic and skeletal manifestations of chronic colitis.
- CRB-15 demonstrates potential as a therapeutic agent for managing IBD-associated weight and bone loss.
- These findings provide a proof-of-concept for targeting IL-15 in IBD treatment strategies.
