Progression of renal disease in interleukin-4 transgenic mice: involvement of transforming growth factor-β

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Abstract
Recent reports have suggested the involvement of interleukin‐4 (IL‐4) in glomerular pathophysiology. Using immunohistochemistry and reverse transcriptase polymerase chain reaction we investigated the renal lesions in transgenic (tg) mice with widely distributed IL‐4 expression including the kidney, and measured the serum levels of the cytokines transforming growth factor‐β (TGF‐β) and IL‐4 by ELISA. Transgenic animals exhibited glomerular hypertrophy with progressive mesangial sclerosis leading to renal failure. Renal IL‐4 transcript expression, mesangial accumulation of collagen types I, III, IV and V, and immune deposition accompanied by increased expression of TGF‐β1 protein and mRNA were observed. Seven day‐old transgenic animals showed early renal fibrotic changes in the absence of immune deposits or TGF‐β1 upregulation. The sera of transgenic mice not only showed elevated levels of circulating IL‐4 (tg: 76.6 pg/ml ± 7.1 vs wildtype (wt): < 3 pg/ml), but significantly decreased TGF‐β1 levels (tg: 18.9 ng/ml ± 4.1 vs wt: 38.7 ng/ml ± 2.9; P < 0.005). The disease severity correlated with the serum IL‐4/TGF‐β1 ratio rather than with the IL‐4 concentration. These data suggest that renal IL‐4 production results in matrix accumulation prior to any immunological insult, that increased circulating IL‐4/TGF‐β1 ratios are associated with renal immunopathological manifestations and that upregulation of renal TGF‐β1 expression following glomerular Ig deposition accelerates the sclerosis and exacerbates disease development.