ABROGATION OF GLOMERULAR INJURY IN NEPHROTOXIC NEPHRITIS BY CONTINUOUS-INFUSION OF INTERLEUKIN-6

Interleukin-6 (IL-6) has been reported to have pro-and anti-inflammato ry effects. It has also been shown to cause mesangial cell proliferati on in vitro and has been suggested as a mediator of injury in prolifer ative nephritis. We have assessed the effects of continuous infusion o f human recombinant (hr) IL-6, by osmotic minipump, on the degree of g lomerular injury, and on glomerular and interstitial cell proliferatio n, in the accelerated autologous phase of nephrotoxic nephritis. Two g roups of rats were pre-immunized with 1 mg of normal rabbit IgG in Fre und's complete adjuvant. One week later, nephritis was induced by an i ntravenous injection of 1 ml of rabbit nephrotoxic serum. One day befo re the induction of nephritis, group 1 (N = 9) was subcutaneously impl anted with osmotic minipumps filled with 50 mu g (200 mu l) of IL-6 (e quivalent to a dose of 6 mu g/day), while in group 2 (N = 11) the mini pumps were filled with 200 mu l of normal saline. In group 3 (N = 6) n ormal rats were infused with 50 mu g of IL-6 alone. The rats were kill ed seven days after implantation of minipumps. The administered hrIL-6 was detectable in the circulation within the pathophysiological range , and induced a hepatic acute phase response, as assessed by alpha 2-m acroglobulin levels. Continuous treatment with nd resulted in a signif icant reduction in albuminuria (from 195 +/- 37 mg/20 hr to 60 +/- 15 mg/20 hr on day 1, and from 494 +/- 52 mg/20 hr to 238 +/- 30 mg/20 hr on day 7, P < 0.002) and in the prevalence of glomerular capillary th rombosis (from 19 +/- 3% to 5 +/- 1%, P < 0.002). There was also a red uction in macrophage infiltration (ED1 + ve cells from 524 +/- 34 to 4 66 +/- 14 per 50 glomeruli, P < 0.02) and activation (ED3 + ve cells f rom 106 +/- 13 to 42 +/- 5 per 50 glomeruli, P < 0.002). Immunohistolo gy showed fewer interstitial Ia + ve cells (OX3 and OX4) in the IL-6 t reated group. Similar results were obtained in a second set of experim ents in which the IL-6 treatment was extended until day 14. Kidney sec tions taken from nephritic rats infused with IL-6 showed no increase i n glomerular or interstitial cell proliferation when stained with anti bodies to proliferating cell nuclear antigen. There was no difference in the deposition of rabbit IgG or rat IgG along the glomerular baseme nt membrane (GBM), and the titer of rat anti-rabbit IgG was similar in the IL-6 and central treated rats. Infusion of IL-6 alone in normal r ats had no functional or pathological effects. In conclusion, these re sults show that IL-6 has powerful anti-inflammatory effects in a rat m odel of anti-GBM nephritis, and does not induce mesangial cell prolife ration in vivo.