Passive immunization against tumour necrosis factor-alpha (TNF-α) and IL-lβ protects from LPS enhancing glomerular injury in nephrotoxic nephritis in rats

Abstract

SUMMARYGlomerular injury caused by injection of heterologous anti-glomerular basement membrane antibodies (anti-GBM Ab) is increased in rats pretreated with small doses of bacterial lipopolysaccharide (LPS). We have Investigated the involvement of tumour necrosis factor-alpha (TNF-a), IL-la and IL-l^in this phenomenon by passive immunization against these cytokines. Anti-TNF-«oranti-IL-l/i antibodies given 15 h before the induction of nephritis significantly decreased injury in this model, whether assessed by the magnitude of albuminuria. the prevalence of giomerular capillary thrombi or the intensity of glomerular neutrophil infiltrate. Aibuminuria in anti-GBM Ab alone was U ±3. LPS/anU-GBM Ab 87 + 22. and anti-TNF-a antibodies/LPS/anti-GBM Ab 21 ±6 mg/24 h (mean + s.e.) /*<0-05. Passiveimmunization with antibodies to IL-l/f had a similar effect (anti-GBM Ab.O-6 + 0-l,LPS/anti-GBM Ab.92+19.anti-IL-l/fantibodies/LPS./anti-GBM Ab39±8mg/24h. P<{)QS). The prevalence of glomerular capillary thrombi was also reduced significantly by these Ircatmcnts; from 22±5% to 4±1% in the case of anti-TNF-a antibodies and 28±5% to 13 ±4% with anti-IL-1 ^antibodies, Similarly, the glomerular neutrophil infiltrate was also reduced by these treatments; from 42 + 3 to 25±1 In the case of anti-TNF-D; and 47±2 to 30+1 with anti-IL-lâ ntibodies. In eontrast, passive immunization againsi IL-la had no effect on either albumin excretion {4 + 3, 83 + 22 and 77 + 24 mg/24 h), glomerular capillary thrombi (2+1; I9±5 and !6±3) or glomerular neutrophil infiltrate (22 + 3; 47 + 5 and 48 + 5 from the three groups respectively). These results demonstrate that enhanced antibody mediated injury in the kidney is modulated by TNF-a and \L-\(i but not by IL-la.Keywords nephrotoxic antibody lipopolysaccharide tumour necrosis factor-alpha interleukin-1 a and P aipha 2-macroglobulln

Simvastatin ameliorates glomerulosclerosis in Adriamycin-induced-nephropathy rats

“…Studies in murine crescentic glomerulonephritis (GN) indicate that IL-1β is the major proinflammatory cytokine-mediating glomerular injury [20]. The benefits of inhibiting IL-1 using anti-IL-1 antibodies [21], soluble IL-1 receptor, or IL-1-receptor antagonist [22] have been shown in experimental GN. Our data revealed that increasing IL-1β expression accompanied severe glomerulosclerosis and renal tubular cell injury in untreated ADR-nephrosis rats, whereas mild and moderate glomerulosclerosis and renal tubular cell injury with weak IL-1β expression were found in the renal tissue of simvastatin-treated ADR-nephrosis rats.…”

Molecular Mechanisms of Nephro-Protective Action of HE-86 Liquid Extract in Experimental Chronic Renal Failure

“…There is a mounting evidence to implicate TNF-in the pathogenesis of glomeruli of rodents with experimental nephritis, and is found in renal biopsies, sera and urine of patients with different types of glomerulonephritis [88][89][90][91]; In vitro and in vivo studies document that TNF-is produced locally within inflamed glomeruli by mesangial and epithelial cells, as well as by infiltrating monocytes/macrophages [89,91]; Systemic administration of TNFresults in glomerular damage in rabbits [92] and exacerbates the degree of glomerular injury in nephrotoxic nephritis in rats [93]; and blocking endogenous TNF-in nephrotoxic nephritis in rats ameliorates acute glomerular inflammation [94], and down-regulates glomerular IL-1 mRNA and circulating TNF-concentrations [95].…”

Glomerulonephritis, Pathogenetic Mechanisms and Therapeutic Options: An Overview

“…Very interesting is the ability to simultaneously inhibit TNF and IL-1, then it is because most of the two cytokines produced by monocytes-macrophages and mesangial cells during activation by immune-mediated GN [67]. At present, the combined use of the two drugs was too burdened by side effects [13,58,59].…”

“…Another approach theoretically very interesting is the use of cytokines that act naturally against the inflammatory process, such as IL -4, IL -1 0 , IL-13 or modest doses of TG -ß1 [58,67,68].…”

“…These drugs have proven useful in experimental rapidly progressive GN, where they inhibited the formation of crescents [61][62][63][64][65][66][67], and in mouse strains having developed spontaneously SLE [68].…”