Role of cyclooxygenase-2 in deoxynivalenol-induced immunoglobulin a nephropathy.
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.
Jia
Qunshan
Q
Department of Food Science and Human Nutrition, Michigan State University, 234 G.M. Trout Building, East Lansing, MI 48824-1224, USA.
Pestka
James J
JJ
D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005922:Glomerulonephritis, IGA / Q000139:chemically induced / Q000209:etiology* / Q000378:metabolism; D007070:Immunoglobulin A / Q000097:blood / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D007783:Lactones / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D011451:Prostaglandin-Endoperoxide Synthases / Q000172:deficiency / Q000502:physiology*; D011897:Random Allocation; D013450:Sulfones / Q000494:pharmacology*; D014255:Trichothecenes / Q000633:toxicity*; D015854:Up-Regulation
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007070:Immunoglobulin A; D015850:Interleukin-6; D007783:Lactones; D013450:Sulfones; D014255:Trichothecenes; C116926:rofecoxib; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C007262:deoxynivalenol