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.

Abstract-IgG Fc receptors (Fc␥Rs) play a role in activating the immune system and in maintaining peripheral tolerance, but their role in atherosclerosis is unknown. We generated double-knockout (DKO) mice by crossing apolipoprotein E-deficient mice (apoE Ϫ/Ϫ ) with Fc␥R ␥ chain-deficient mice (␥ Ϫ/Ϫ ). The size of atherosclerotic lesions along the aorta was approximately 50% lower in DKO compared with apoE Ϫ/Ϫ control mice, without differences in serum lipid levels. The macrophage and T-cell content of lesions in the DKO were reduced by 49Ϯ6% and 56Ϯ8%, respectively, compared with the content in apoE Ϫ/Ϫ lesions. Furthermore, the expression of monocyte chemoattractant protein-1 (MCP-1), RANTES (Regulated on Activated Normal T-cell Expressed and Secreted), and intercellular adhesion molecule-1 (ICAM-1) and the activation of nuclear factor-B (NF-B) were significantly reduced in aortic lesions from DKO mice. In vitro, vascular smooth muscle cells (VSMCs) from both ␥ Ϫ/Ϫ and DKO mice failed to respond to immune complexes, as shown by impaired chemokine expression and NF-B activation. ApoE Ϫ/Ϫ mice have higher levels of activating Fc␥RI and Fc␥RIIIA, and inhibitory Fc␥RIIB, compared with wild-type mice. The DKO mice express only the inhibitory Fc␥RIIB receptor. We conclude that Fc␥R deficiency limits development and progression of atherosclerosis. In addition to leukocytes, Fc␥R activation in VSMCs contributes to the inflammatory process, in part, by regulating chemokine expression and leukocyte invasion of the vessel wall. These results underscore the critical role of Fc␥Rs in atherogenesis and support the use of immunotherapy in the treatment of this disease. Key Words: Fc receptors Ⅲ atherosclerosis Ⅲ double-knockout mice Ⅲ immune complexes A therosclerosis is a chronic inflammatory disease of the arterial wall characterized by progressive accumulation of lipids, cells, and extracellular matrix. In recent years, the immune processes associated to atherogenesis have received considerable attention. Studies in both humans and animals have demonstrated that atheromatous lesions at all stage of development contain a wide variety of cells and molecules characteristic of immune system, such as macrophages, lymphocytes, CD40, interferon-␥, major histocompatibility complex-II, complement, and antibodies (Abs). [1][2][3][4] In addition, congenital deficiency of macrophages, T and B lymphocytes, or even the inhibition of their mediators has resulted in the reduction of atherosclerotic lesion. 1,3 One of the critical steps in atherogenesis is the accumulation within the arterial intima of cholesteryl ester-laden foam cells, many of them derived from macrophages, whose formation is ultimately dependent on the uptake of various forms of low-density lipoproteins (LDLs). 1,2 Although emphasis has been placed on scavenger receptors, foam-cell development may also be influenced by lipoprotein interaction with other receptors, such as LDL receptors, very-low-density lipoprotein (VLDL) receptors, and IgG Fc (Fc␥Rs) receptors. 5 Diff...

NF-kappaB inhibition by PTN retards atherosclerotic lesions in apoE mice, by reducing lesion size and changing plaque composition. This natural compound could represent a novel therapeutic approach to inflammation during vascular damage.