2004), overexpressed LTBP-1 could participate in maintaining high levels of TGF-�� in the fibrotic nodule, a location from which it could be eventually activated. Although the expression of TGF-�� and LTBP-1 at the mRNA and protein considering levels should be coordinated, there is some controversy on this issue. Whereas erythroleukaemia, foreskin fibroblast and breast cancer human cell lines express TGF-�� and LTBP-1 coordinately after treatment with exogenous TGF-��, certain osteoblast-like cell lines regulate TGF-�� and LTBP-1 expression in an independent manner. Furthermore, a human glioblastoma cell line has been described that secretes active TGF-�� in the absence of LTBP (Miyazono et al. 1991; Olofsson et al. 1992; Dallas et al. 1994; Koli & Keski-Oja 1995).

In this regard, exogenous TGF-�� treatment increased LTBP-1 mRNA in AhR wild-type MEFs, but neither exogenous TGF-�� nor the addition of TGF-�� antibodies had any effect on LTBP-1 mRNA in AhR-null MEFs. The role of the AhR as a negative regulator of LTBP-1 expression in MEF cells could be also extrapolated in vivo to the periportal areas of the liver. Because the expression of the fibroblast marker protein ��-actin was coincident with fibrosis and with LTBP-1 overexpression in the periportal areas of AhR?/? liver, it could be suggested that the fibroblast cells present in such area, in the absence of AhR, could produce higher levels of LTBP-1 and TGF-��, thus leading to collagen deposition and fibrosis. In agreement with these data, recent results have suggested that biliary fibrosis could result from a transdifferentiation process involving portal fibroblasts and hepatic stellate cells (Wells et al.

2004). Although LTBP-1 has been traditionally considered as a localization protein for TGF-��, it has also been lately considered as a component of the ECM (Koli et al. 2001). Elevated levels of LTBP-1 in the ECM have also been reported in several fibrotic conditions, such as allograft arteriosclerosis and tuberculous pleurisy (Maeda et al. 1993; Waltenberger et al. 1993a, 1993b) and in patients suffering from chronic hepatitis C (Kinnman et al. 2000). According to this, AhR-null MEFs, grown post confluently, had an excess of LTBP-1 deposition in their ECM (Santiago-Josefat et al. 2004) that could be similar to that observed in the periportal ECM of the fibrotic areas of AhR-null livers.

All these data suggest not only that LTBP-1 has an important role in TGF-��-mediated fibrosis, but also that the AhR is an important regulator of both LTBP-1 and TGF-�� activities. A relevant issue is the mechanism by which the AhR modulates LTBP-1 expression. GSK-3 It is possible that the AhR, as a transcription factor, could regulate LTBP-1 expression by direct binding to its promoter. To address this possibility, gene reporter studies are underway to identify putative regulatory elements for AhR binding on the mouse LTBP-1 gene.