Abstract
Complement plays a key role in the pathophysiology of many inflammatory diseases, and in this study, we investigated the role of complement in the pathogenesis of inflammatory bowel disease. Compared to wild-type mice, mice deficient in C3 or factor B were protected from acute dextran sulfate sodium (DSS)-induced colitis. C1q/mannose-binding lectin (MBL) double-deficient mice, however, exhibited more severe colitis than wild-type mice. When mice were allowed to recover after DSS treatment, all C1q/MBL(-/-) mice died by day 2 of recovery period, and, surprisingly, all C3(-/-) and factor B(-/-) mice died by day 5. Serum endotoxin levels were significantly increased in complement-deficient mice prior to death, particularly in C1q/MBL(-/-) mice, and antibiotic treatment prevented the lethal effect of DSS in all complement-deficient mice. In contrast to complement deficiency, targeted complement inhibition with either complement receptor 2 (CR2)-Crry (blocks all pathways at C3 activation) or CR2-factor H (blocks alternative pathway) was highly protective at treating established acute colitis. Endotoxin levels remained low in complement-inhibited mice, and complement inhibition also reduced inflammatory cytokines, leukocyte infiltrat...Continue Reading
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