Modulation of antibody-mediated glomerular injury in vivo by bacterial lipopolysaccharide, tumor necrosis factor, and IL-1.
We have investigated the effects of LPS, human rTNF (hrTNF) and human rIL-1 beta (hrIL-1 beta) pretreatment on the intensity of antibody-mediated injury in vivo by using a passive model of anti-glomerular basement membrane (GBM) antibody-mediated nephritis in rats. The experiments show that all three pretreatments exacerbate injury in this model whether judged by albuminuria or the prevalence of glomerular capillary thrombi. The effect on albuminuria was dose dependent with all three treatments. The lowest effective dose of LPS was 0.025 microgram while those for hrTNF and hrIL-1 beta were 0.4 microgram and 0.5 microgram, respectively. All three pretreatments also increased the prevalence of glomerular capillary thrombi which were rare in rats injected with anti-GBM antibodies without pretreatment. LPS pretreatment appeared to be more effective in causing glomerular capillary thrombi than hrTNF or hrIL-1 beta and this was reflected in the correlations between albuminuria and the proportion of glomeruli with capillary thrombi. This relation was linear for all three pretreatments but the slope was appreciably greater for rats pretreated with LPS (0.37) when compared with results from rats given either hrTNF (0.22) or hrIL-1 beta (0.29). Pretreatment of nephritic rats with both cytokines increased the slope to 0.42 demonstrating a synergistic effect. The synergism of hrTNF with hrIL-1 beta was also demonstrated by the effective doses needed to induce albuminuria which was evident in rats treated with 0.05 microgram of IL-1 beta and 0.4 microgram of TNF. Neither the cytokines nor LPS caused clinical, morphologic, or biochemical evidence of renal toxicity when given alone in the dose used here but they did cause a transient increase in the number of neutrophils marginated in glomerular capillaries. Pretreatment of rats with LPS or cytokines increased the glomerular neutrophil influx after anti-GBM antibodies by roughly sixfold. Our experiments show that TNF and IL-1 can increase the severity of glomerular injury in nephritis; they may be important in modulating glomerular injury clinically.
Tomosugi
N I
NI
Department of Medicine, Royal Postgraduate Medical School, London.
Cashman
S J
SJ
Hay
H
H
Pusey
C D
CD
Evans
D J
DJ
Shaw
A
A
Rees
A J
AJ
D000419:Albuminuria / Q000209:etiology; D000818:Animals; D001323:Autoantibodies / Q000008:administration & dosage / Q000502:physiology*; D001485:Basement Membrane / Q000276:immunology; D005921:Glomerulonephritis / Q000209:etiology / Q000473:pathology; D006801:Humans; D007375:Interleukin-1 / Q000633:toxicity*; D007678:Kidney Glomerulus / Q000276:immunology / Q000473:pathology*; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D009504:Neutrophils / Q000473:pathology; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*
D001323:Autoantibodies; D007375:Interleukin-1; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha