Article Text
Abstract
Background and aims: Interleukin-12 (IL-12), a p35/p40 heterodimer, plays a pivotal role in the immune response in Crohn’s disease (CD). Since IL-12 p40 dimers act as IL-12 antagonists, we assayed p40 dimer proteins to modulate chronic intestinal inflammation.
Methods: We generated a fusion protein consisting of the IL-12(p40) subunit fused to the constant region of IgG2b. IL-12(p40)-IgG2b was tested in a murine 2,4,6,-trinitrobenzene sulphonic acid (TNBS) colitis model and in lamina propria mononuclear cells (LPMNC) from patients with CD in vitro.
Results: Dimeric IL-12(p40)-IgG2b fusion protein bound specifically to the IL-12 receptor. In concentrations <10−7 M, it acted as an IL-12 antagonist as it inhibited interferon γ (IFN-γ) secretion, suppressed proliferation, and increased apoptosis of LPMNC from patients with CD. However, in concentrations >10−6 M, IL-12(p40)-IgG2b increased IFN-γ secretion and lymphocyte proliferation thereby acting as an IL-12 agonist. In TNBS colitic mice, IL-12(p40)-IgG2b decreased mortality (10% v 68%), prevented body weight loss, reduced tumour necrosis factor α, and increased IL-10 secretion.
Conclusions: The IL-12(p40)-IgG2b fusion protein has dichotomic properties as a specific IL-12 antagonist and selective repressor of mucosal inflammation at low concentration and as an IL-12 agonist at high concentration.
- interleukin 12
- fusion protein
- Crohn’s disease
- inflammatory bowel disease
- 5-ASA, 5-aminosalicylic acid
- CD, Crohn’s disease
- TNBS, 2,4,6,-trinitrobenzene sulphonic acid
- LPMNC, lamina propria mononuclear cells
- PBMNC, peripheral blood mononuclear cells
- IL, interleukin
- IFN-γ, interferon γ
- mAb, monoclonal antibody
- PCR, polymerase chain reaction
- PBS, phosphate buffered saline
- PMA, phorbol myristate acetate
- PBL, peripheral blood lymphocytes
- TNF-α, tumour necrosis factor α
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- 5-ASA, 5-aminosalicylic acid
- CD, Crohn’s disease
- TNBS, 2,4,6,-trinitrobenzene sulphonic acid
- LPMNC, lamina propria mononuclear cells
- PBMNC, peripheral blood mononuclear cells
- IL, interleukin
- IFN-γ, interferon γ
- mAb, monoclonal antibody
- PCR, polymerase chain reaction
- PBS, phosphate buffered saline
- PMA, phorbol myristate acetate
- PBL, peripheral blood lymphocytes
- TNF-α, tumour necrosis factor α