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 potential of transforming growth factor-beta 1 (TGF-beta 1) in the renal glomerulus. 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 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-1 beta. To examine whether glomeruli which express active TGF-beta 1 in vivo are insensitive to these same stimuli, TGF-beta transfectants were transferred into normal rat glomeruli via renal artery injection. After 24 hours, isolated glomeruli containing transfectants exhibited TGF-beta bioactivity, a reduced mitogenic response, and repressed expression of MMP-9 in response to IL-1 beta. We further examined the responses of these chimeric glomeruli to an in vivo mitogenic stimulus by transferring TGF-beta 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-beta transfectants was significantly repressed. Furthermore, cellular outgrowth from nephritic glomeruli expressing active TGF-beta 1 was also suppressed ex vivo compared to controls. These data indicate that TGF-beta 1 inhibits mitogenesis and IL-1 response of the glomerulus and may, in part, act as a potential early suppressor of glomerular inflammation.
Kitamura
M
M
Department of Medicine, University College London Medical School, England, United Kingdom.
Burton
S
S
English
J
J
Kawachi
H
H
Fine
L G
LG
D000818:Animals; D015152:Blotting, Northern; D002478:Cells, Cultured; D018014:Gene Transfer Techniques; D005920:Glomerular Mesangium / Q000166:cytology / Q000502:physiology*; D007375:Interleukin-1 / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism; D008938:Mitosis / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*
D007375:Interleukin-1; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D008666:Metalloendopeptidases