SUPPRESSION OF EXPERIMENTAL GLOMERULONEPHRITIS BY THE INTERLEUKIN-1 RECEPTOR ANTAGONIST - INHIBITION OF INTERCELLULAR-ADHESION MOLECULE-1 EXPRESSION

Interleukin-1 is a proinflammatory cytokine produced in glomerulonephr itis. Blocking the action of interleukin-1 by the administration of th e interleukin-1 receptor antagonist (IL-1ra) has been shown to prevent renal function impairment, reduce glomerular injury, inhibit leukocyt e infiltration, and suppress tubulointerstitial damage in experimental antiglomerular basement membrane disease. A key mechanism in the entr y of leukocytes into the kidney is the interaction between the interle ukin-1 inducible intercellular adhesion molecule-1 (ICAM-1; CD54) and lymphocyte function-associated antigen-1 (CD11a/CD18). Therefore, this study investigated whether the inhibition of this mechanism was the m eans by which IL-1ra suppressed leukocyte infiltration in rat accelera ted antiglomerular basement membrane glomerulonephritis. Disease was i nduced in two groups of six rats; animals were treated by constant sc infusion of recombinant human IL-1ra or saline from the initiation of disease until being euthanized 14 days later. In saline-treated animal s, there was marked up-regulation of ICAM-1 in the glomerulus and inte rstitium, which was associated with leukocyte infiltration. In particu lar, focal accumulation of CD1 1a(+) and CD18(+) cells was apparent in areas of tubulointerstitial damage exhibiting intense ICAM-1 expressi on. IL-1ra treatment partially reduced glomerular ICAM-1 expression an d leukocyte infiltration. However, IL-1ra treatment resulted in a dram atic inhibition of interstitial ICAM-1 expression, interstitial leukoc yte infiltration, and tubulointerstitial damage. In conclusion, this s tudy has shown that interleukin-1 is a major inducer of ICAM-1 express ion within the renal tubulointerstitium-a process associated with foca l leukocyte infiltration and tubulointerstitial damage. This is the fi rst demonstration of a specific mechanism by which interleukin-1 parti cipates in the pathogenesis of renal injury.