Properdin Deficiency Protects from 5-fluorouracil-induced Small Intestinal Mucositis in a Complement activation Independent but IL-10 Dependent Mechanism

We used properdin deficiency to interrogate the impact of complement in mucositis, a dose-limiting side effect of anti-cancer drugs that in particular damages the epithelium. C57BL/6 (WT), IL-10^-/-, properdin knockout (P^KO) or IL-10/properdin double knockout (DKO) mice were injected daily with 5-fluorouracil (5-FU). The animals’ weight and presence of rectal blood was recorded. Twenty four hours after the last injection serum and small intestines were collected. During 5 days of 5-FU injections both WT and P^KO mice lost weight; however, at the end of the regimen P^KO mice had less rectal bleeding. C3a and C5a were significantly increased in intestines of both strains indicating complement was activated, yet the histology revealed that P^KO mice were less inflamed. Additionally, P^KO mice had less intestinal TNF and higher IL-10 levels (IL-1β was unchanged and IL-6 and interferon-γ undetectable). We reasoned that if increased IL-10 is necessary for protection in P^KO mice then DKO mice ought to be as susceptible as IL-10^-/- mice to mucositis, and this proved to be true. Thus while complement is activated during mucositis, properdin deficiency protects from mucositis in a complement activation-independent, IL-10-dependent mechanism.  Further investigation is required to determine if blocking complement can de-couple mucositis from the cancer cell target of chemotherapeutic drugs.