Transforming growth factor-beta inhibition of interleukin-1 activity involves down-regulation of interleukin-1 receptors on chondrocytes.
Interleukin-1 (IL-1) plays an important role in cartilage destruction associated with inflammatory and degenerative arthritis because of its ability to induce matrix degrading enzymes. Previously, we have shown that the IL-1-induced chondrocyte protease activity was inhibited by transforming growth factor-beta (TGF-beta). In this paper, we show that TGF-beta inhibits the IL-1-induced synthesis of collagenase and stromelysin by reducing the steady-state mRNA levels in rabbit articular chondrocytes. We further demonstrate that TGF-beta-treated chondrocytes show reduced 125I-IL-1 binding that returns to a normal level when TGF-beta is removed from the culture medium. The inhibitory effect of TGF-beta is observed for both naturally occurring as well as fibroblast growth factor (FGF)-inducible binding sites (receptors). Scatchard analysis of receptor-ligand interactions demonstrate that the reduced binding is due to a reduction in the number of receptors for IL-1 and is not due to changes in affinity. Affinity cross-linking studies suggest that control chondrocytes contain two major cross-linked bands of Mr = 116 and 80 kDa and a minor band of Mr = 100 kDa. FGF-treated cells show enhanced levels of all the bands, plus an additional 200-kDa band. TGF-beta treatment of chondrocytes results in the reduction of all of these bands in both control as well as FGF-induced cells. These observations suggest that the ability of TGF-beta to down-regulate the IL-1 receptor may be a mechanism by which it exerts its effects in antagonizing the IL-1 activity on chondrocytes.
Harvey
A K
AK
Department of Rheumatology, Lilly Research Laboratories, Corporate Center, Indianapolis, Indiana 46285.
Hrubey
P S
PS
Chandrasekhar
S
S
D000818:Animals; D001483:Base Sequence; D002356:Cartilage / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D003432:Cross-Linking Reagents; D004247:DNA; D015536:Down-Regulation; D004792:Enzyme Precursors / Q000096:biosynthesis; D007375:Interleukin-1 / Q000378:metabolism*; D019278:Matrix Metalloproteinase 3; D008666:Metalloendopeptidases / Q000096:biosynthesis / Q000378:metabolism; D003012:Microbial Collagenase / Q000378:metabolism; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D011971:Receptors, Immunologic / Q000378:metabolism*; D017472:Receptors, Interleukin-1; D016212:Transforming Growth Factor beta / Q000502:physiology*
D003432:Cross-Linking Reagents; D004792:Enzyme Precursors; D007375:Interleukin-1; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; D016212:Transforming Growth Factor beta; D004247:DNA; D008666:Metalloendopeptidases; C052706:neutral proteinase, cervical; C048047:prostromelysin; D019278:Matrix Metalloproteinase 3; D003012:Microbial Collagenase