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The Journal of Immunology, 1998, 161: 4992-4999.
Copyright © 1998 by The American Association of Immunologists

Role of IL-6 and the Soluble IL-6 Receptor in Inhibition of VCAM-1 Gene Expression1

Jae-Wook Oh*, Nicholas J. Van Wagoner*, Stefan Rose-John{dagger} and Etty N. Benveniste2,*

* Department of Cell Biology, University of Alabama, Birmingham, AL; and {dagger} Section of Pathophysiology, First Department of Medicine, University of Mainz, Mainz, Germany

Adhesion molecules such as VCAM-1 and ICAM-1 are increased in the central nervous system (CNS) during inflammatory responses and contribute to extravasation of leukocytes across the blood-brain barrier (BBB) and into CNS parenchyma. Astrocytes contribute to the structural integrity of the BBB and can be induced to express VCAM-1 and ICAM-1 in response to cytokines such as TNF-{alpha}, IL-1ß, and IFN-{gamma}. In this study, we investigated the influence of IL-6 on astroglial adhesion molecule expression. IL-6, the soluble form of the IL-6R (sIL-6R), or both IL-6 plus sIL-6R, had no effect on VCAM-1 or ICAM-1 gene expression. Interestingly, the IL-6/sIL-6R complex inhibited TNF-{alpha}-induced VCAM-1 gene expression but did not affect TNF-{alpha}-induced ICAM-1 expression. The inhibitory effect of IL-6/sIL-6R complex was reversed by the inclusion of anti-IL-6R and gp130 Abs, demonstrating the specificity 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, also 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 unexpected negative effect on adhesion molecule expression in glial cells and may function as an immunosuppressive cytokine within the CNS.




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