Abstract
Ingestion of the trichothecene mycotoxin deoxynivalenol (DON) induces serum IgA elevation and kidney mesangial IgA deposition in a manner that mimics the early stages of IgA nephropathy (IgAN), the most common human glomerulonephritis. Previous studies indicate that elevated interleukin-6 (IL-6) expression is crucial for this model and that DON induction of cyclooxygenase-2 (COX-2) might drive IL-6 upregulation. We hypothesized that COX-2 and its metabolites are essential for DON-induced IgAN and thus might be a suitable target for prophylaxis against aberrant IgA upregulation. DON feeding studies using COX-2 knockout mice or the COX-2 specific inhibitor, rofecoxib (Vioxx), were employed to test the hypothesis. Study 1 results demonstrated that DON consumption induced serum IgA and IgA-immune complex (IC) accumulation, IgA kidney deposition and splenic IgA secretion in wild-type mice. COX-2 deficiency did not affect upregulation of these parameters but rather, promoted DON-induced serum IgA elevation. Study 2 demonstrated that rofecoxib could not block DON-induced serum IgA, serum IgA-IC and mesangial IgA accumulation but instead increased enhanced serum IgA upregulation. These corroborating results suggest that COX-2 is not a requisite for DON-induced IgAN and furthermore, that COX-2 inhibitors such as rofecoxib would be contraindicated for the prevention of early stages of IgAN.
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