title: IL-12p40 and IL-18 in crescentic glomerulonephritis: IL-12p40 is the key Th1-defining cytokine chain, whereas IL-18 promotes local inflammation and leukocyte recruitment.
abstract: Experimental crescentic glomerulonephritis (GN) is characterized by T helper 1 (Th1) directed nephritogenic immune responses and cell-mediated glomerular injury. IL-12p40, the common cytokine chain for both IL-12 and IL-23, is important in the generation and potentially the maintenance of Th1 responses, whereas IL-18 is a co-factor for Th1 responses that may have systemic and local proinflammatory effects. For testing the hypothesis that both endogenous IL-12p40 and endogenous IL-18 play pathogenetic roles in crescentic GN, accelerated anti-glomerular basement membrane GN was induced in mice genetically deficient in IL-12p40 (IL-12p40-/-), IL-18 (IL-18-/-), or both IL-12p40 and IL-18 (IL-12p40-/-IL-18-/-). Compared with wild-type C57BL/6 mice, IL-12p40-/- mice failed to make a nephritogenic Th1 response and developed markedly reduced crescent formation and renal leukocytic infiltration, despite renal production of chemoattractants and adhesion molecules. IL-18-/- mice developed an intact antigen-specific systemic Th1 response, a similar degree of crescent formation, but fewer glomeruli affected by other severe histologic changes and fewer leukocytes in glomeruli and interstitium. IL-18 was expressed within diseased kidneys. Local production of TNF, IL-1beta, IFN-gamma, CCL3 (MIP-1alpha), and CCL4 (MIP-1beta) was reduced in IL-18-/- mice, demonstrating a local proinflammatory role for IL-18. Combined deletion of IL-12p40 and IL-18 did not result in synergistic effects. Consistent with the hypothesis that inflammation leads to fibrosis, all three groups of deficient mice expressed lower levels of intrarenal TGF-beta1 and/or alpha1(I) procollagen mRNA. These studies demonstrate that in severe experimental crescentic GN, IL-12p40 is the key Th1-defining cytokine chain, whereas IL-18 has local proinflammatory roles.
authors.affiliation: Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia. richard.kitching@med.monash.edu.au
authors.forename: A Richard
authors.initials: AR
authors.lastname: Kitching
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Turner
authors.forename: Gabrielle R A
authors.initials: GR
authors.lastname: Wilson
authors.forename: Timothy
authors.initials: T
authors.lastname: Semple
authors.forename: Dragana
authors.initials: D
authors.lastname: Odobasic
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Timoshanko
authors.forename: Kim M
authors.initials: KM
authors.lastname: O'Sullivan
authors.forename: Peter G
authors.initials: PG
authors.lastname: Tipping
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takeda
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Holdsworth
mesh_terms: D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D007111:Immunity, Cellular; D018664:Interleukin-12 / Q000235:genetics / Q000502:physiology*; D053762:Interleukin-12 Subunit p40; D020382:Interleukin-18 / Q000235:genetics / Q000502:physiology*; D007678:Kidney Glomerulus / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D021122:Protein Subunits / Q000235:genetics / Q000502:physiology*; D018417:Th1 Cells / Q000276:immunology / Q000502:physiology*
chemical_list: D015815:Cell Adhesion Molecules; D016207:Cytokines; D053762:Interleukin-12 Subunit p40; D020382:Interleukin-18; D021122:Protein Subunits; D018664:Interleukin-12