Modulation of antibody-mediated glomerular injury in vivo by interleukin-6.
We have shown previously that pretreatment with small doses of bacterial lipopolysaccharide (LPS), human recombinant interleukin-1 beta (hrIL-1 beta) and human recombinant tumor necrosis factor-alpha (hrTNF) increase injury in the heterologous phase of nephrotoxic nephritis (NTN). All three pretreatments induce synthesis of interleukin-6 (IL-6) which in some systems down-regulates synthesis of IL-1 and TNF. We have now investigated the influence of IL-6 on injury in both heterologous and autologous phases of NTN in rats. Injection of hrIL-6 in doses sufficient to induce hepatic synthesis of acute phase proteins (assessed by plasma alpha 2-macroglobulin concentration) had no effect on glomerular injury in the heterologous phase of NTN (albuminuria in NTAb alone 9 +/- 6; LPS/NTAb 34 +/- 10 and IL-6/NTAb 2 +/- 1 mg/24 hr, P < 0.001, Wilcoxon test). In contrast, IL-6 pretreatment partially abrogated the effect of LPS on albumin excretion (NTAb 4 +/- 2; LPS/NTAb 85 +/- 11 and IL-6/LPS/NTAb 32 +/- 6 mg/24 hr, P < 0.002), percentage of glomerular capillary thrombi (3 +/- 1%; 39 +/- 8%; and 6 +/- 1%, P < 0.001) and glomerular neutrophil infiltrate (29 +/- 3; 58 +/- 5; and 34 +/- 2 neutrophils/50 glomeruli in section, P < 0.001, respectively) at 24 hours. The effect of IL-6 was also evident four hours after induction of nephritis and was associated with a marked reduction in glomerular concentration of mRNA for IL-1 beta and TNF, without change in that of tubulin. Serum TNF concentrations were also significantly reduced at four hours in IL-6 treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Karkar
A M
AM
Department of Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, London, England, United Kingdom.
Tam
F W
FW
Proudfoot
A E
AE
Meager
A
A
Rees
A J
AJ
D000818:Animals; D000906:Antibodies / Q000502:physiology*; D007275:Injections, Intravenous; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology*; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009393:Nephritis / Q000139:chemically induced / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000906:Antibodies; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha