title: Interleukin-6 exacerbates glomerulonephritis in (NZB x NZW)F1 mice.
abstract: The ability of interleukin-6 (IL-6) to modulate immune parameters and mesangial cell function suggests a role for this cytokine in the development of autoimmune glomerulonephritis. This hypothesis was tested in 6-month-old female (NZB x NZW)F1 mice that were administered recombinant human IL-6 (rhIL-6) (50 and 250 micrograms/kg s.c.) for 12 weeks, resulting in an accelerated and severe form of membranoproliferative glomerulonephritis associated with marked upregulation of mesangial major histocompatibility 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, (NZB x NZW)F1 mice were immunosuppressed with cyclosporin. Immunosuppression by cyclosporin inhibited the development of glomerulonephritis, decreased class II antigen expression, and abrogated IL-6-mediated effects. Administration of neutralizing anti-IL-6 antibody had no effect on the spontaneous development of glomerulonephritis in (NZB x NZW)F1 mice. This finding, together with undetectable IL-6 serum levels, makes a pathogenetic role of endogenously produced IL-6 in this disease model unlikely. In contrast to (NZB x NZW)F1 mice, parental NZW or BALB/c mice given high doses of rhIL-6 (500 micrograms/kg) or recombinant murine IL-6 (100 micrograms/kg) daily for 4 weeks failed to develop morphological or biochemical evidence of glomerulonephritis. Induction of acute phase proteins, anemia, thrombocytosis, and induction of renal class II antigen confirmed the biological activity of IL-6 in these mice. In conclusion, while non-nephritogenic in normal mice, IL-6 accelerates the development of the genetically determined glomerulonephritis of (NZB x NZW)F1 mice through effects mediated by a modulated immune system. Since neutralizing IL-6 antibody treatment did not prevent the development of glomerulonephritis, it is unlikely that increased IL-6 production plays a role in the pathogenesis of lupus nephritis.
authors.affiliation: Institute of Toxicology, Faculty of Medicine, University of Zurich, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Ryffel
authors.forename: B D
authors.initials: BD
authors.lastname: Car
authors.forename: H
authors.initials: H
authors.lastname: Gunn
authors.forename: D
authors.initials: D
authors.lastname: Roman
authors.forename: P
authors.initials: P
authors.lastname: Hiestand
authors.forename: M J
authors.initials: MJ
authors.lastname: Mihatsch
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001682:Biological Availability; D016572:Cyclosporine / Q000494:pharmacology; D005260:Female; D005921:Glomerulonephritis / Q000209:etiology* / Q000401:mortality / Q000473:pathology; D006681:HLA-D Antigens / Q000187:drug effects / Q000378:metabolism; D015850:Interleukin-6 / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008814:Mice, Inbred NZB; D008854:Microscopy, Electron; D011507:Proteinuria / Q000209:etiology; D013045:Species Specificity; D015996:Survival Rate; D000093242:Interleukin-6 Inhibitors
chemical_list: D000906:Antibodies; D016572:Cyclosporine; D006681:HLA-D Antigens; D015850:Interleukin-6; D000093242:Interleukin-6 Inhibitors