Suppression of Experimental Crescentic-Type Anti-Glomerular Basement Membrane (GBM) Nephritis by FK506 (Tacrolimus Hydrate) in Rats

Abstract

ABSTRACT-The effect of FK506 (tacrolims hydrate), an immunosuppressive agent produced by Strepto myces tsukubaensis, on crescentic-type anti-glomerular basement membrane (GBM) nephritis in rats was investigated. When rats were treated with FK506 from 1 or 20 days after the anti-GBM serum injection, FK506 inhibited the increase in urinary protein excretion. Histological observation demonstrated that FK506 suppressed glomerular alterations. In the FK506-treated rats, antibody production and rat-IgG and C3 deposits on the GBM were significantly less than those in the nephritic control group. FK506 treatment suppressed the accumulation of ED-1-positive cells, CD4-positive cells, CD8-positive cells, interleukin-2 (IL-2)-receptor-positive cells, leukocyte-function-associated antigen-1 (LFA-1)-positive cells and intercellu lar adhesion molecule-1 (ICAM-1)-expression in nephritic glomeruli. However, in the in vitro study, FK506 failed to inhibit the up-regulated ICAM-1 expression on endothelial cells in response to tumor necrosis factor (TNF)-a. On the other hand, IL-2 production from the spleen cells isolated from nephritic rats treated with FK506 was lower than that in the nephritic control rats. These results suggest that FK506 is effective against crescentic-type anti-GBM nephritis and that the antinephritic mechanisms of FK506 is due to the inhibition of intraglomerular accumulation and activation of leukocytes through the suppression of ICAM-1 expression and IL-2 production.

Saireito and Saikosaponin D Prevent Urinary Protein Excretion via Glucocorticoid Receptor in Adrenalectomized WKY Rats with Heterologous-Phase Anti-GBM Nephritis

“…There is evidence that glucocorticoids inhibit IL-2 and IL-10 production stimulated by anti-CD3, LPS, or PHA [21, 22]. Moreover, it is known that increases in the IL-2 level in the glomeruli in nephritis induced by heterogeneous antibody injection and suppression of IL-2 function, particularly local suppression in the kidney, lead to improvement of nephritis [23, 24]. The mechanisms by which Th1 cytokines affect the consequent inflammatory cascade that is caused by glomerular injury, such as proteinuria or histopathological changes, remain unclear.…”

Tacrolimus suppresses tumour necrosis factor‐α and protects against splanchnic artery occlusion shock

“…Thus transcription of several proinflammatory cytokines, including Interleukin‐1 (IL‐1) and Tumour Necrosis Factor (TNF‐α) is inhibited ( Ray et al ., 1990 ; Guyre et al ., 1988 ). Indeed tacrolimus has been shown to affect endotoxin‐induced pathologies ( Hattori & Nakanishi, 1995 ; Whitcup et al ., 1998 ), nitric oxide generation as a predictive parameter of acute allograft rejection ( Devlin et al ., 1994 ), Intercellular adhesion molecule 1 (ICAM‐1) expression ( Arreaza et al ., 1995 ; Hayashi et al ., 1996 ) and nitric oxide generation in smooth muscle cells ( Akita et al ., 1994 ).…”