Transforming growth factor-beta inhibition of cytokine-induced vascular cell adhesion molecule-1 expression in human...

Leukocyte transmigration across the blood-brain barrier (BBB) is a cardinal feature of central nervous system (CNS) inflammation. Astrocytes form an integral part, both structurally and functionally, of the BBB. Vascular cell adhesion molecule-1 (VCAM-1), a member of the immunoglobulin gene superfamily, is involved in extravasation into inflamed tissues and activation of T-lymphocytes. In this study, we investigated the role of TGF-beta, an immunosuppressive cytokine, in regulating cytokine-induced VCAM-1 expression in astrocytes. Human astroglioma cell lines and primary human fetal astrocytes were examined for VCAM-1 gene expression after treatment with proinflammatory cytokines (TNF-alpha, IL-1beta, IFN-gamma) in the absence or presence of TGF-beta. Astroglioma cell lines as well as primary human fetal astrocytes expressed low levels of VCAM-1 constitutively, and the proinflammatory cytokines induced marked increases in VCAM-1 expression, particularly TNF-alpha and IL-1beta. The inclusion of TGF-beta1 or TGF-beta2 with the proinflammatory cytokines inhibited VCAM-1 gene expression to varying degrees (33-93%) in all the astroglioma cell lines and primary fetal cells. These results indicate that TGF-beta is an important regulator of cytokine induced VCAM-1 expression on astrocytes and may prove useful clinically in controlling CNS inflammation.