ROLE OF IL-6 AND THE SOLUBLE IL-6 RECEPTOR IN INHIBITION OF VCAM-1 GENE-EXPRESSION

Adhesion molecules such! as VCAM-1 and ICAM-1 are increased in the cen tral nervous system (CNS) during inflammatory responses and contribute to extravasation of leukocytes across the blood-brain barrier (BBB) a nd into CNS parenchyma. Astrocytes contribute to the structural integr ity of the BBB and can be induced to express VCAM-1 and ICAM-1 in resp onse to cytokines such as TNF-alpha, IL-1 beta, and IFN-gamma, In this study, we investigated the influence of IL-6 on astroglial adhesion m olecule expression, IL-6, the soluble form of the IL-6R (sIL-6R), or b oth IL-6 plus sIL-6R, had no effect on VCAM-1 or ICAM-1 gene expressio n. Interestingly, the IL-6/sIL-6R complex inhibited TNF-alpha-induced VCAM-1 gene expression but did not affect TNF-alpha-induced ICAM-1 exp ression, The inhibitory effect of n-6/sIL-6R complex was reversed by t he inclusion of anti-IL-6R and gp130 Abs, demonstrating the specificit y of the response. A highly active fusion protein of sIL-6R and IL-6, covalently linked by a flexible peptide, which is designated H-IL-6, a lso inhibited TNF alpha-induced VCAM-1 expression, sIL-6R alone was an effective inhibitor of TNF-alpha-induced VCAM-1 due to endogenous IL- 6 production, These results indicate that the IL-6 system has an unexp ected negative effect on adhesion molecule expression in glial cells a nd may function as an immunosuppressive cytokine within the CNS.