INTERLEUKIN-6 EXACERBATES GLOMERULONEPHRITIS IN (NZBXNZW)F-1 MICE

The ability of interleukin-6 (IL-6) to modulate immune parameters and mesangial cell function suggests a role for this cytokine in the devel opment of autoimmune glomerulonephritis. This hypothesis was tested in 6-month-old female (NZBxNZW)F-1 mice that were administered recombina nt human IL-6 (rhIL-6) (50 and 250 mu/kg s.c.) for 12 weeks, resulting in an accelerated and severe form of membranoproliferative glomerulon ephritis associated with marked upregulation of mesangial major histoc ompatibility complex class II antigen and glomerular ICAM-1 expression . To distinguish direct effects of rhIL-6 on the renal mesangium from those mediated through the immune system, (NZBxNZW)F-1 mice were immun osuppressed with cyclosporin. Immunosuppression by cyclosporin inhibit ed the development by cyclosporin inhibited the development of glomeru lonephritis, decreased class II antigen expression, and abrogated IL-6 -mediated effects. Administration of neutralizing anti-IL-6 antibody h ad no effect on the spontaneous development of glomerulonephritis in ( NZBxNZW)F-1 mice. This finding, together with undetectable IL-6 serum levels, makes a pathogenetic role of endogenously produced IL-6 in thi s disease model unlikely. In contrast to (NZBxNZW)F-1 mice, parental N ZW or BALB/c mice given high doses of rhIL-6 (500 mu g/kg) or recombin ant murine IL-6 (100 mu g/kg) daily for 4 weeks failed to develop morp hological or biochemical evidence of glomerulonephritis. Induction of acute phase proteins, anemia, thrombocytosis, and induction of renal c lass II antigen confirmed the biological activity of IL-6 in these mic e. In conclusion, while non-nephritogenic in normal mice, IL-6 acceler ates the development of the genetically determined glomerulonephritis of (NZBxNZW)F-1 mice through effects mediated by a modulated immune sy stem. Since neutralizing IL-6 antibody treatment did not prevent the d evelopment of glomerulonephritis, it is unlikely that increased IL-6 p roduction plays a role in the pathogenesis of lupus nephritis.