Dysregulated transforming growth factor-beta in neonatal and adult autoimmune MRL-lpr mice

Transforming growth factor-beta (TGF-beta) is a cytokine that promotes inflammatory processes and prevents tissue injury. Autoimmune destruction of the kidney in MRL-lpr mice is spontaneous, rapid, fatal and consists of glomerular damage and an influx of lymphocytes surrounding vessels and in the interstitium. In MRL-lpr mice, cytokine dysregulation is apparent in neonates and continues throughout the life span. Circulating levels of tumour necrosis factor (TNF-alpha) and colony stimulating factor-1 (CSF-1) are detected in neonatal mice and progressively increase in proportion to the loss of renal function. We now report elevated intracellular expression of distinct isoforms of TGF-beta (TGF-beta 3, TGF-beta 2, and TGF-beta 1) detected immunohistochemically in MRL-lpr kidneys and other tissues including the liver and thymus. Enhanced TGF-beta 3 and TGF-beta 2 isoforms are detectable in neonatal mice within the renal tubular epithelial cells (TEC) and vascular smooth muscle cells (VSMC). In MRL-lpr mice 4-6 months of age, TGF-beta 3, TGF-beta 2 and TGF-beta 1 are detected in TEC, VSMC, glomerular epithelial cells (GEC) and in perivascular infiltrating cells. By comparison, TGF-beta is minimally detectable in the normal kidneys of age and sex matched MRL-++ or C3H/FeJ mice. Paradoxically, in vitro cultured TEC and VSMC from MRL-lpr mice secrete less TGF-beta than TEC and VSMC isolated from MRL-++ or C3H/FeJ mice. TNF-alpha, but not IL-6, CSF-1, or IFN-gamma stimulated the secretion of TGF-beta in TEC and VSMC. Our data demonstrate the dysregulation of TGF-beta isoforms in neonatal and adult MRL-lpr mice prior to and after the onset of autoimmune renal disease. We suggest that TNF-alpha and/or other molecules increase TGF-beta expression in MRL-lpr mice. We speculate that enhanced expression of TGF-beta promotes autoimmune renal injury in MRL-lpr mice. (C) 1996 Academic Press Limited