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  • Title: Dysregulated transforming growth factor-beta in neonatal and adult autoimmune MRL-lpr mice.
    Author: Kreft B, Yokoyama H, Naito T, Kelley VR.
    Journal: J Autoimmun; 1996 Aug; 9(4):463-72. PubMed ID: 8864821.
    Abstract:
    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 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(-)+2 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(-)+2 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 autoinmune renal injury in MRL-lpr mice.
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