Modulation of antibody-mediated glomerular injury in vivo by IL-1ra, soluble IL-1 receptor, and soluble TNF receptor

Abstract

The severity of glomerular injury in the heterologous phase of NTN is dependent on proinflammatory cytokines including TNF alpha and IL-1 beta, and can be enhanced by LPS. We have previously shown that passive immunization against IL-1 beta and TNF partially abrogated the LPS effect in this model. In the present work, we have assessed the effects on glomerular injury of blocking and binding of IL-1 to its receptor by rh IL-1 receptor antagonist (IL-1ra) and by neutralizing IL-1 and TNF with rm soluble IL-1 receptor type1 (sIL-1Rt1) and rh sTNF receptor (sTNFr p55), respectively. Pretreatment with either IL-1ra, sIL-1Rt1, or sTNFr partially abrogated the effects of LPS and reduced albumin excretion from 45 +/- 8, 66 +/- 9, and 101 +/- 17 mg/24 hr at 13 +/- 4 (P < 0.02), 14 +/- 4 (P < 0.001), and 21 +/- 7 mg/24 hr (P < 0.001), respectively. Similarly, these inhibitors reduced the prevalence of glomerular capillary thrombi and the intensity of glomerular neutrophil infiltration. Glomerular thrombosis was reduced from 18 +/- 3%, 28 +/- 5%, and 25 +/- 7% to 3 +/- 2% (P < 0.002), 6 +/- 2% (P < 0.001), and 3 +/- 2 (P < 0.001), respectively, and glomerular neutrophil infiltration was reduced from 46 +/- 3, 54 +/- 2, 59 +/- 8 to 19 +/- 2 (P < 0.001), 25 +/- 2 (P < 0.001), and 28 +/- 2 neutrophils/50 glomeruli in section, respectively. Coadministration of both soluble receptors of IL-1 and TNF caused a further decrease in glomerular injury. The protective effect was also noticed at four hours after induction of nephritis, and even when these inhibitors were administered after the LPS injection and at the same time of induction of nephritis. All three treatments reduced circulating TNF concentration (down to 20%, 34%, and 0%, respectively) but without detectable glomerular TNF gene expression. Glomerular IL-1 beta mRNA levels were also reduced by 41%, 53%, and 67%, respectively, when assessed by densitometric analysis of Northern blots. In contrast, the glomerular expression of IL-1ra was not affected by its exogenous administration but was mildly reduced by sIL-1Rt1 and sTNFr, which demonstrates the potential role for host derived IL-1ra as an endogenous negative feedback mediator in the glomerulus. These results confirm the direct involvement of IL-1 and TNF in LPS-enhanced hNTN and demonstrate the potency of these inhibitors in modulating injury even when administered after LPS and in time of induction of nephritis. They were more specific and effective than passive immunization with polyclonal antibodies, and this demonstrates their potential usefulness in the management of nephritis.

Patrolling monocytes promote intravascular neutrophil activation and glomerular injury in the acutely inflamed glomerulus

“…Inhibition of TNF resulted in a significant inhibition of renal injury, as shown by a >50% reduction in urinary albumin: creatinine ratio (Fig. 7C), consistent with previously published results in similar models (31,32). Similarly, inhibition of CXCL1 also resulted in a significant reduction in urinary albumin: creatinine ratio (Fig.…”

“…Of these mediators, TNF has been previously identified as a critical mediator in in situ immune complexmediated glomerulonephritis, via its promotion of adhesion molecule expression and glomerular barrier breakdown (31,32). TNF is also a potent and rapid inducer of ROS production via stimulation of NAPDH oxidase activity in neutrophils (39), a pathway we have previously shown to be responsible for glomerular dysfunction in acute glomerular inflammation (20).…”

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.…”

Intrinsic Renal Cells Are the Major Source of Tumor Necrosis Factor Contributing to Renal Injury in Murine Crescentic Glomerulonephritis

“…In experimental GN, administration of soluble TNF receptors to rats developing crescentic GN reduced glomerular injury and prevented crescent formation (4,5). Anti-TNF antibodies (Ab) attenuate acute heterologous phase antiglomerular basement membrane (GBM) Ab-induced injury in rats (3).…”