Properdin Regulation of Complement Activation Affects Colitis in Interleukin 10 Gene-Deficient Mice.
BACKGROUND
Interleukin 10-deficient mice (IL-10(-/-)) are a popular model used to dissect the mechanisms underlying inflammatory bowel diseases. The role of complement, a host defense mechanism that bridges the innate and adaptive immune systems, has not been described in this model. We therefore studied the effect of deficiency of properdin, a positive regulator of complement, on colitis in mice with the IL-10(-/-) background.


METHODS
For acute colitis, IL-10(-/-) and IL-10/properdin double knockout (DKO) or radiation bone marrow-reconstituted chimeric mice, had piroxicam added to their powdered chow for 14 days. For chronic colitis, 2.5% dextran sodium sulfate was added to the animals' water for 4 days then the mice were killed 8 weeks later. Colons were assessed for inflammation, cell infiltration, and cytokine and complement measurements. Bacterial translocation was measured by cultivating bacteria from organs on Luria broth agar plates.


RESULTS
C3a and C5a levels and C9 deposition were all increased in piroxicam-fed IL-10(-/-) mice compared with mice not fed piroxicam. Piroxicam-fed DKO mice lacked increased C5a and C9 deposition combined with exacerbated colitis, reduced numbers of infiltrating neutrophils, and markedly higher local and systemic bacterial numbers compared with IL-10(-/-) mice. Bone marrow cells from IL-10(-/-) mice were sufficient to restore protection against the heightened colitis in piroxicam-fed DKO mice.


CONCLUSIONS
Complement is activated in the IL-10(-/-) mouse mucosa in a properdin-dependent manner. In the absence of terminal complement activation, the inflammation is heightened, likely due to a lack of neutrophil control over microbes escaping from the intestines.
Departments of *Microbiology and Immunology, and †Pathology, Dalhousie University, Halifax, NS, Canada; ‡Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom; and §Department of Pediatrics, Dalhousie University, Halifax, NS, Canada.
Umang
U
Jain
Craig A
CA
Midgen
Wilhelm J
WJ
Schwaeble
Cordula M
CM
Stover
Andrew W
AW
Stadnyk
D000818:Animals; D002478:Cells, Cultured; D002908:Chronic Disease; D003092:Colitis / Q000378:metabolism*; D003167:Complement Activation; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011414:Properdin / Q000378:metabolism*
D011414:Properdin; D016753:Interleukin-10