occurs during hepatic fibrosis and cirrhosis. 1,2,5 TGF-b stim-SEE EDITORIAL ON PAGE 1067 ulates SCs to transform into myofibroblast-like cells, enhances their production of extracellular matrix proteins, [1][2][3][4] Liver stellate cells (SCs) play central roles in both the storand alters the degradation of the extracellular matrix. 1,6 TGFage of retinol and the development of liver fibrosis. The pres-b suppresses the growth and function of hepatocytes, at least ent study is aimed to understand the mechanism by which in part, by down-regulating the production of hepatocyte retinoic acid (RA, an active metabolite of retinol) enhances growth factor in SCs. 7 hepatic fibrosis in rats. We tested the effect of 9-cis-RA on Three subtypes of TGF-b (TGF-b 1 , -b 2 , and -b 3 ), whose several aspects in vitro rat SC cultures, including the activity biological properties are nearly identical, are found in mamof cellular plasminogen activator (PA), messenger RNA malians. 8 TGF-bs are synthesized and secreted in a biologi-(mRNA), and protein levels of transforming growth factor-b cally latent form (latent TGF-b: 235-280 kd) which must be (TGF-b) mRNA level of type-I procollagen, and the activity activated before it can bind to receptors and perform biologiof type-I collagenase. Employing the rat liver fibrosis model cal activities. 8,9 Latent TGF-b 1 consists of the following three produced by porcine serum, we also estimated the effect of components: the active TGF-b 1 homodimer, the paired TGForal administration of a stable RA analog on the progression b 1 propeptide (also known as the latency-associated peptide), of the fibrosis, as well as on hepatic TGF-b contents. In vitro and the latent TGF-b 1 binding protein. The 25-kd homodi-SC cultures, 9-cis-RA enhanced cellular PA and plasmin levels meric active TGF-b is noncovalently associated with latencythereby induced plasmin-mediated activation of latent TGFassociated peptide (75 kd), and latency-associated peptide, b. Active TGF-b generated self-stimulated its synthesis as in turn, is disulfide-bonded to latent TGF-b 1 binding protein well as that of collagen and suppressed the production of (range, 135-180 kd). Activation releases the 25-kd TGF-b collagenase in an autocrine manner. In in vivo rat models, an molecule from the large complex. In vitro, the latent TGF-b RA analog accelerated the porcine serum-induced fibrosis by can be activated through physical means, such as transient enhancing TGF-b contents and, thus, collagen levels in the acidification (pH 3), which disrupts the noncovalent interacliver, although the RA analog alone was not fibrogenic. These tions between TGF-b and latency-associated peptide, 8,10 or results suggest that RA exacerbated liver fibrosis, at least in by proteases, especially plasmin, which may cleave latencypart, by inducing the activation and production of latent TGFassociated peptide within its amino-terminal region and reb in liver SCs. (HEPATOLOGY 1997;26:913-921.) lease active TGF-b. 10
Plasmin-mediated activation also occurs under physiologi-Transforming growth factor-b (TGF-b) is the major cytocal conditions such as in the co-cultures of endothelial and kine implicated in the pathogenesis of liver fibrosis and cirsmooth muscle cells. 9,11,12 In this system, activation occurs rhosis. [1][2][3][4] Hepatic stellate cells (SCs) are responsible for much at the cell-surface by plasmin generated from serum plasminof the collagen hypersecretion and nodule formation that ogen by the action of plasminogen activator (PA). 12,13 Latent TGF-b molecules are localized to the cell surface and/or Abbreviations: SCs, stellate cells; RA, retinoic acid; PA, plasminogen activator; matrix by binding to the cation-independent mannose-6-mRNA, messenger RNA; TGF-b, tumor growth factor b; BSA, bovine serum albumin; phosphate/insulin-like growth factor-II receptor, through DMEM, Dulbecco's modified Eagle's medium; GAPDH, glyceraldehyde-3-phosphate mannose-6-phosphate-containing carbohydrates in the ladehydrogenase.