IL-12p40 and IL-18 in Crescentic Glomerulonephritis

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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-1β, IFN-γ, CCL3 (MIP-1α), and CCL4 (MIP-1β) 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-β1 and/or α1(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.