Tranilast inhibits interleukin-1beta-induced monocyte chemoattractant protein-1 expression in rat mesangial cells.

Monocyte chemoattractant protein-1 (MCP-1), a member of the CC subfamily of chemokines, plays a crucial role in the progression of glomerulonephritis by recruitment of monocytes. Tranilast, a clinically used anti-allergic drug, has been demonstrated to have various anti-inflammatory and anti-proliferative effects, and recently has been reported to prevent restenosis after percutaneous transluminal coronary angioplasty. In this study, we investigated whether tranilast inhibits MCP-1 secretion in mesangial cells. Tranilast inhibited interleukin-1beta-induced MCP-1 secretion and mRNA expression in a concentration-dependent manner. Luciferase assay showed that tranilast suppressed interleukin-1beta-induced nuclear factor-kappaB (NF-kappaB)-dependent transcription. Interleukin-1beta-induced Jun N-terminal kinase (JNK) activation was also suppressed selectively by tranilast. These results indicate that tranilast inhibits interleukin-1beta-induced MCP-1 production, at least in part, by inhibiting NF-kappaB activity and that suppression of JNK activation might be involved in the inhibition of MCP-1 production. Tranilast may serve as a new therapeutic agent for glomerulonephritis through anti-chemokine property.

Overexpression of truncated I kappa B alpha potentiates TNF-alpha-induced apoptosis in mesangial cells.

BACKGROUND: Dysregulation of apoptosis is one of the likely underlying mechanisms of mesangial proliferative glomerulonephritis (GN), a disease in which proinflammatory cytokines exhibit a wide range of biological activities. Among them, tumor necrosis factor-alpha (TNF-alpha) induces two conflicting pathways, one leading to activation of the nuclear factor-kappa B (NF-kappa B), and the other leading to caspase-mediated apoptosis. We investigated whether or not specific inhibition of NF-kappa B affects TNF-alpha-induced apoptosis in rat mesangial cells (MCs). METHODS: To specifically inhibit NF-kappa B activation, we constructed a recombinant adenovirus vector expressing a truncated form of I kappa B alpha (AdexI kappa B delta N) that lacks the phosphorylation sites essential for the activation of NF-kappa B. Electrophoretic mobility shift assay was performed to evaluate NF-kappa B activity. Nuclear morphology was observed by staining with Hoechst-33258. DNA fragmentation was detected using an ELISA kit with an antihistone antibody. To investigate the regulation of apoptosis, we measured caspase-3 and caspase-8 activity by ELISA, and examined the Bcl-2 and Bax protein level by Western blot. RESULTS: TNF-alpha-induced NF-kappa B activation was blocked by overexpression of I kappa B delta N. Overexpression of I kappa B delta N potentiated TNF-alpha-induced apoptosis compared to mock transfection, and the potentiation was abolished by treatment with a caspase-3 inhibitor, Z-DEVD-FMK. Overexpression of I kappa B delta N augmented TNF-alpha-induced caspase-3 and caspase-8 activity, but did not affect Bcl-2 or Bax protein expression. CONCLUSION: Overexpression of I kappa B delta N potentiates TNF-alpha-induced apoptosis and augments caspase-8 and caspase-3 activity in rat MCs without changing Bcl-2 or Bax protein expression. These results suggest the potential usefulness of AdexI kappa B delta N to induce apoptosis in MCs under inflammatory conditions.

[Case of MPO-ANCA positive interstitial pneumonitis and necrotizing, crescentic glomerulonephritis].

A 52-year-old man was admitted to our hospital in July 1995, because of intermittent claudication, paresthesia on foot and gross hematuria. Chest radiograph in 1988 revealed bilateral interstitial shadows and proteinuria had been pointed out since 1992. On admission, chest X-ray and computed tomography showed diffuse interstitial shadow, however it had not been changed for several years. Laboratory tests revealed elevated level of erythrocyte sedimentation rate, C-reactive protein, immunoglobulin, rheumatoid factor, IgG-rheumatoid factor, and immune complex. Serum MPO-ANCA were positive. Although serum creatinine level and renal function test were normal, renal biopsy demonstrated crescentic formation and necrotizing vasculitis. Immunofluorescence and electron microscopy demonstrated no remarkable deposit in glomerulus. A diagnosis of microscopic polyarteritis necrotizing and crescentic glomerulonephritis (NCGN) was made. Treatment was initiated with 30 mg of prednisolone, followed by marked improvement of intermittent claudication, and decreased titer of serum MPO-ANCA. Previous reports have demonstrated the association of MPO-ANCA with rapidly progressive NCGN, microscopic polyarteritis, and occasionally pulmonary hemorrhage recognized as pulmonary-renal syndrome. However, the present case suggests the possibility that another disease subset may also be associated with MPO-ANCA, which is characterized by interstitial pneumonitis and slowly progressive glomerulonephritis.