Properdin deficiency protects from 5-fluorouracil-induced small intestinal mucositis in a complement activation-independent, interleukin-10-dependent mechanism

Jain, U., Midgen, C. A., Woodruff, T. M., Schwaeble, W. J., Stover, C. M. and Stadnyk, A. W. (2017) Properdin deficiency protects from 5-fluorouracil-induced small intestinal mucositis in a complement activation-independent, interleukin-10-dependent mechanism. Clinical and Experimental Immunology, 188 1: 36-44. doi:10.1111/cei.12922


Author Jain, U.
Midgen, C. A.
Woodruff, T. M.
Schwaeble, W. J.
Stover, C. M.
Stadnyk, A. W.
Title Properdin deficiency protects from 5-fluorouracil-induced small intestinal mucositis in a complement activation-independent, interleukin-10-dependent mechanism
Journal name Clinical and Experimental Immunology   Check publisher's open access policy
ISSN 1365-2249
0009-9104
Publication date 2017-04-01
Sub-type Article (original research)
DOI 10.1111/cei.12922
Open Access Status Not yet assessed
Volume 188
Issue 1
Start page 36
End page 44
Total pages 9
Place of publication Chichester, West Sussex, United Kingdom
Publisher Wiley-Blackwell Publishing
Language eng
Formatted abstract
Intestinal mucositis is a serious complication of chemotherapy that leads to significant morbidity that may require dose or drug adjustments. Specific mitigating strategies for mucositis are unavailable, due partly to an incomplete understanding of the pathogenic mechanisms. We have previously shown an effect of properdin, a positive regulator of complement activation, in models of colitis. Here we use properdin-deficient (PKO) mice to interrogate the role of properdin and complement in small intestinal mucositis. Mucositis was induced by five daily injections of 5-fluorouracil (5-FU) in wild-type (WT), PKO, interleukin (IL)-10-/- and properdin/IL-10-/- double knock-out (DKO) mice. At the time of euthanasia their jejunum was collected for histology, immunohistochemistry and cytokine and complement activation measurements. Complement became activated in mice receiving 5-FU, indicated by increased intestinal levels of C3a and C5a. Compared to WT, PKO mice experienced significantly less mucositis, despite C3a levels as high as inflamed WT mice and slightly less C5a. Conversely, PKO mice had higher intestinal levels of IL-10. IL-10 expression was mainly by epithelial cells in both uninflamed and inflamed PKO mice. IL-10-/- mice proved to be highly susceptible to mucositis and DKO mice were equally susceptible, demonstrating that a lack of properdin does not protect mice lacking IL-10. We interpret our findings to indicate that, to a significant extent, the inflammation of mucositis is properdin-dependent but complement activation-independent. Additionally, the benefit achieved in the absence of properdin is associated with increased IL-10 levels, and IL-10 is important in limiting mucositis.
Keyword 5-fluorouracil
Anaphylatoxin
Chemotherapy
Mucositis
Properdin
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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