MODULATION OF ANTIBODY-MEDIATED GLOMERULAR INJURY IN-VIVO BY IL-1RA, SOLUBLE IL-1 RECEPTOR, AND SOLUBLE TNF RECEPTOR

The severity of glomerular injury in the heterologous phase of NTN is dependent on proinflammatory cytokines including TNF alpha and IL-1 be ta, and can be enhanced by LPS. We have previously shown that passive immunization against IL-1 beta and TNF partialy abrogated the LPS effe ct in this model. In the present work, we have assessed the effects on glomerular injury of blocking the 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 (s TNFr p55), respectively. Pretreatment with either IL-1ra, sIL-1Rt1, or sTNFr partially abrogated the effects of LPS and reduced albumin excr etion from 45 +/- 8, 66 +/- 9, and 101 +/- 17 mg/24 hr to 13 +/- 4 (P < 0.02), 14 +/- 4 (P < 0.001), and 21 +/- 7 mg/24 hr (P < 0.001), resp ectively. Similarly, these inhibitors reduced the prevalence of glomer ular capillary thrombi and the intensity of glomerular neutrophil infi ltration. 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, and 59 +/- 8 to 19 +/- 2 (P < 0.0 01), 25 +/- 2 (P < 0.001), and 28 +/- 2 neutrophils/50 glomeruli in se ction, respectively. Coadministration of both soluble receptors of IL- 1 and TNF caused a further decrease in glomerular injury. The protecti ve effect was also noticed at four hours after induction of nephritis, and even when these inhibitors were administered after the LPS inject ion and at the same time of induction of nephritis. All three treatmen ts reduced circulating TNF concentration (down to 20%, 34%, and 0%, re spectively) but without detectable glomerular TNF gene expression. Glo merular IL-1 beta mRNA levels were also reduced by 41%, 53%, and 67%, respectively, when assessed by densitometric analysis of Northern blot s. In contrast, the glomerular expression of IL-1ra was not affected b y its exogenous administration but was mildly reduced by sIL-1Rt1 and sTNFr, which demonstrates the potential role for host derived IL-1ra a s an endogenous negative feedback mediator in the glomerulus. These re sults confirm the direct involvement of IL-1 and TNF in LPS-enhanced h NTN and demonstrate the potency of these inhibitors in modulating inju ry even when administered after LPS and at time of induction of nephri tis. They were more specific and effective than passive immunization w ith polyclonal antibodies, and this demonstrates their potential usefu lness in the management of nephritis.