TRANSFER OF A MUTATED GENE ENCODING ACTIVE TRANSFORMING GROWTH-FACTOR-BETA-1 SUPPRESSES MITOGENESIS AND IL-1 RESPONSE IN THE GLOMERULUS

Using in vivo gene transfer, we examined the anti-inflammatory potenti al of transforming growth factor-beta 1 (TGF-beta 1) in the renal glom erulus. TGF-beta 1 cDNA, modified to allow for secretion of the active form of TGF-beta 1, was introduced into cultured rat mesangial cells. The responses of the established transfectants were examined in cultu re. In vitro, the transduced mesangial cells showed a reduced mitogeni c response to fetal calf serum and were insensitive to induction of ma trix metalloproteinase-9 (MMP-9) by the proinflammatory cytokine IL-1 beta. To examine whether glomeruli which express active TGF-beta 1 in vivo are insensitive to these same stimuli, TGF-beta transfectants wer e transferred into normal rat glomeruli via renal artery injection. Af ter 24 hours, isolated glomeruli containing transfectants exhibited TG F-beta bioactivity, a reduced mitogenic response, and repressed expres sion of MMP-9 in response to IL-1 beta. We further examined the respon ses of these chimeric glomeruli to an in vivo mitogenic stimulus by tr ansferring TGF-beta transfectants into glomeruli of kidneys one day af ter the induction of anti-Thy-1 nephritis. The mitogenic activity of i solated glomeruli was examined four days after the cell injection. Com pared to unmodified or mock cell-containing glomeruli, the in vivo mit ogenic activity of glomeruli containing TGF-beta transfectants was sig nificantly repressed. Furthermore, cellular outgrowth from nephritic g lomeruli expressing active TGF-beta 1 was also suppressed ex vivo comp ared to controls. These data indicate that TGF-beta 1 inhibits mitogen esis and IL-1 response of the glomerulus and may, in part, act as a po tential early suppressor of glomerular inflammation.