Progression of renal disease in interleukin-4 transgenic mice: involvementof transforming growth factor-beta

Recent reports have suggested the involvement of interleukin-4 (IL-4) in gl omerular pathophysiology. Using immunohistochemistry and reverse transcript ase polymerase chain reaction we investigated the renal lesions in transgen ic (tg) mice with widely distributed IL-4 expression including the kidney, and measured the serum levels of the cytokines transforming growth factor-b eta (TGF-beta) and IL-4 by ELISA. Transgenic animals exhibited glomerular hypertrophy with progressive mesang ial sclerosis leading to renal failure. Renal IL-4 transcript expression, m esangial accumulation of collagen types I, III, IV and V, and immune deposi tion accompanied by increased expression of TGF-beta 1 protein and mRNA wer e observed. Seven day-old transgenic animals showed early renal fibrotic ch anges in the absence of immune deposits or TGF-beta 1 upregulation. The ser a of transgenic mice not only showed elevated levels of circulating IL-4 (t g: 76.6 pg/ml +/- 7.1 vs wildtype (wt): < 3 pg/ml), but significantly decre ased TGF-beta 1 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-beta 1 r atio rather than with the IL-4 concentration. These data suggest that renal IL-4 production results in matrix accumulatio n prior to any immunological insult, that increased circulating IL-4/TGF-be ta 1 ratios are associated with renal immunopathological manifestations and that upregulation of renal TGF-beta 1 expression following glomerular Ig d eposition accelerates the sclerosis and exacerbates disease development.