IL-1beta depresses expression of the 70-kilodalton heat shock protein and sensitizes glomerular cells to oxidant-initiated apoptosis.
The 70-kDa heat shock protein (hsp70) is induced by several physical stimuli, whereas little is understood about the regulation and function of this molecule during inflammation. We found that the proinflammatory cytokine IL-1beta depressed hsp70 expression in glomerular mesangial cells and that IL-1-pretreated cells were more susceptible to apoptotic death triggered by oxidant stress. To examine whether the altered expression of hsp70 causes the effect of IL-1beta on apoptosis, rat mesangial cells were stably transfected with a hsp70 cDNA under the control of a constitutively active regulatory element. Compared with mock-transfected cells, the established cells overexpressing hsp70 showed resistance to the effect of IL-1beta. The effects of IL-1beta on hsp70 expression and apoptosis were also examined in isolated rat glomeruli. Consistent with the results from mesangial cells, IL-1beta repressed the expression of hsp70 and enhanced the oxidant-initiated apoptosis in the glomerulus. The relationship between glomerular hsp70 and apoptosis was further investigated using an experimental model of anti-glomerular basement membrane glomerulonephritis in which IL-1 and oxidants play crucial roles. Compared with normal expression, the expression of hsp70 was significantly reduced in the inflamed glomeruli. Furthermore, the nephritic glomeruli exhibited oligonucleosomal DNA fragmentation typical of apoptosis. These findings suggested a novel mechanism by which IL-1 may induce glomerular injury. IL-1beta has the potency to affect intrinsic cytoprotective machinery and thereby sensitizes glomerular cells to oxidant-initiated apoptosis. We identified hsp70 as a potential molecular target in this process.
Yokoo
T
T
Department of Medicine, University College London Medical School, The Rayne Institute, United Kingdom.
Kitamura
M
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D002478:Cells, Cultured; D018076:DNA, Complementary; D005786:Gene Expression Regulation / Q000187:drug effects; D005920:Glomerular Mesangium / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D007375:Interleukin-1 / Q000494:pharmacology*; D008297:Male; D016877:Oxidants / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection
D018076:DNA, Complementary; D018840:HSP70 Heat-Shock Proteins; D007375:Interleukin-1; D016877:Oxidants