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Interleukin ( IL)-17 A is increased both in serum and in kidney biopsies from patients with lupus nephritis, but direct evidence of pathogenicity is less well established. Administration of pristane to genetically intact mice results in the production of autoantibodies and proliferative glomerulonephritis, resembling human lupus nephritis. These studies sought to define the role of IL-17 A in experimental lupus induced by pristane administration. Pristane was administered to wild-type ( WT) and IL-17 A−/− mice. Local and systemic immune responses were assessed after 6 days and 8 weeks, and autoimmunity, glomerular inflammation and renal injury were measured at 7 months. IL-17 A production increased significantly 6 days after pristane injection, with innate immune cells, neutrophils ( Ly6 G+) and macrophages ( F4/80+) being the predominant source of IL-17 A. After 8 weeks, while systemic IL-17 A was still readily detected in WT mice, the levels of proinflammatory cytokines, interferon ( IFN)-γ and tumour necrosis factor ( TNF) were diminished in the absence of endogenous IL-17 A. Seven months after pristane treatment humoral autoimmunity was diminished in the absence of IL-17 A, with decreased levels of immunoglobulin ( Ig)G and anti-ds DNA antibodies. Renal inflammation and injury was less in the absence of IL-17 A. Compared to WT mice, glomerular IgG, complement deposition, glomerular CD4+ T cells and intrarenal expression of T helper type 1 ( Th1)-associated proinflammatory mediators were decreased in IL-17 A−/− mice. WT mice developed progressive proteinuria, but functional and histological renal injury was attenuated in the absence of IL-17 A. Therefore, IL-17 A is required for the full development of autoimmunity and lupus nephritis in experimental SLE, and early in the development of autoimmunity, innate immune cells produce IL-17A. [ABSTRACT FROM AUTHOR]

Summary Experimental crescentic glomerulonephritis is driven by systemic cellular immune responses. A pathogenic role for T helper type 1 (Th1) and Th17 cells is well established. T-bet, a key transcription factor required for Th1 lineage commitment, and retinoic acid-related orphan receptor-γt (Rorγt), a key Th17 transcription factor, are required for full expression of disease. Similarly, several Th1- and Th17-associated cytokines have been implicated in disease augmentation. The role of Th2 cells in the disease is less clear, although Th2-associated cytokines, interleukin (IL)-4 and IL-10, are protective. We sought to determine the role of signal transducer and activation of transcription 6 (STAT6), a key regulator of Th2 responses, in experimental crescentic glomerulonephritis. Compared to wild-type mice, histological and functional renal injury was enhanced significantly in STAT6-/- mice 21 days after administration of sheep anti-mouse glomerular basement membrane globulin. Consistent with the enhanced renal injury, both Th1 and Th17 nephritogenic immune responses were increased in STAT6-/- mice. Conversely, production of IL-5, a key Th2-associated cytokine, was decreased significantly in STAT6-/- mice. Early in the disease process systemic mRNA expression of T-bet and Rorγ was increased in STAT6-/- mice. We conclude that STAT6 is required for attenuation of Th1 and Th17 nephritogenic immune responses and protection from crescentic glomerulonephritis. [ABSTRACT FROM AUTHOR]