Nuclear factor-kappa B inhibitors as potential novel anti-inflammatory agents for the treatment of immune glomerulonephritis.
Nuclear factor (NF)-kappa B regulates several genes implicated in the inflammatory response and represents an interesting therapeutic target. We examined the effects of gliotoxin (a fungal metabolite) and parthenolide (a plant extract), which possess anti-inflammatory activities in vitro, on the progression of experimental glomerulonephritis. In the anti-Thy 1.1 rat model, gliotoxin (75 micro g/rat/day, 10 days, n = 18 rats) markedly reduced proteinuria, glomerular lesions, and monocyte infiltration. In anti-mesangial cell nephritis in mice, parthenolide (70 micro g/mouse/day, 7 days, n = 17 mice) significantly decreased proteinuria, hematuria, and glomerular proliferation. NF-kappa B activity, localized in glomerular and tubular cells, was attenuated by either gliotoxin or parthenolide, in association with diminished renal expression of monocyte chemoattractant protein-1 and inducible nitric oxide synthase. In cultured mesangial cells and monocytes, gliotoxin and parthenolide inhibited NF-kappa B activation and expression of inflammatory genes induced by lipopolysaccharide and cytokines, by blocking the phosphorylation/degradation of the I kappa B(alpha) subunit. In summary, gliotoxin and parthenolide prevent proteinuria and renal lesions by inhibiting NF-kappa B activation and expression of regulated genes. This may represent a novel approach for the treatment of immune and inflammatory renal diseases.
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000187:drug effects; D005912:Gliotoxin / Q000494:pharmacology; D005920:Glomerular Mesangium / Q000187:drug effects / Q000473:pathology; D005922:Glomerulonephritis, IGA / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015432:Glomerulonephritis, Membranoproliferative / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D007249:Inflammation; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D011507:Proteinuria / Q000517:prevention & control; D051381:Rats; D012717:Sesquiterpenes / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018932:Chemokine CCL2; D016328:NF-kappa B; D012717:Sesquiterpenes; C002669:parthenolide; D005912:Gliotoxin; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat