Transfer of a mutated gene encoding active transforming growth factor-β1 suppresses mitogenesis and IL-1 response in the glomerulus

Transfer of a mutated gene encoding active transforming growth factor-β1 suppresses mitogenesis and IL-1 response in the glomerulus. Using in vivo gene transfer, we examined the anti-inflammatory potential of transforming growth factor-β1 (TGF-β1) in the renal glomerulus. TGF-β1 cDNA, modified to allow for secretion of the active form of TGF-β1, was introduced into cultured rat mesangial cells. The responses of the established transfectants were examined in culture. In vitro, the transduced mesangial cells showed a reduced mitogenic response to fetal calf serum and were insensitive to induction of matrix metalloproteinase-9 (MMP-9) by the proinflammatory cytokine IL-1β. To examine whether glomeruli which express active TGF-β1 in vivo are insensitive to these same stimuli, TGF-β transfectants were transferred into normal rat glomeruli via renal artery injection. After 24 hours, isolated glomeruli containing transfectants exhibited TGF-β bioactivity, a reduced mitogenic response, and repressed expression of MMP-9 in response to IL-1β. We further examined the responses of these chimeric glomeruli to an in vivo mitogenic stimulus by transferring TGF-β transfectants into glomeruli of kidneys one day after the induction of anti-Thy-1 nephritis. The mitogenic activity of isolated glomeruli was examined four days after the cell injection. Compared to unmodified or mock cell-containing glomeruli, the in vivo mitogenic activity of glomeruli containing TGF-β transfectants was significantly repressed. Furthermore, cellular outgrowth from nephritic glomeruli expressing active TGF-β1 was also suppressed ex vivo compared to controls. These data indicate that TGF-β1 inhibits mitogenesis and IL-1 response of the glomerulus and may, in part, act as a potential early suppressor of glomerular inflammation.