Interleukin-6 production in "normal" and HTLV-1 tax-expressing brain-specific endothelial cells.
Abnormal cytokine production can contribute in many instances to the development of pathology. Our study focuses on the regulation of interleukin (IL)-6 production in vitro in brain-specific endothelial cells (BEC) under physiological conditions and in a model of human T leukemia virus-1 (HTLV-1) infection. IL-6 production was strongly up-regulated in a dose-dependent mode upon exposure to recombinant IL-1 beta, although nearly not detectable in unstimulated BEC. This induction of IL-6 production could be achieved by reagents known to increase intracellular levels of cAMP, such as forskolin, prostaglandin E or pentoxifylline. Furthermore, transcription and production of IL-6 was inducible by addition of dibutyryl cAMP, but not by addition of calcium ionophores or diacylglycerol. To assess a potential role of HTLV-1-infected BEC in the pathogenesis of tropical spastic paraparesis (TSP), the HTLV-1 tax gene was expressed in BEC. Tax gene-expressing BEC produced constitutively very high amounts of IL-6, which were not longer hyperinducible by IL-1 beta or cAMP derivatives. Our results indicate that HTLV-1 tax induces hyperproduction of IL-6 in brain-specific endothelial cells directly by an intracellular mechanism which subsequently renders IL-6 production independent of exogenous stimuli or activators of (cAMP-dependent) second messenger levels. On the basis of these findings we suggest that tax-mediated hyperactivation of IL-6 production in BEC contributes to elevated IL-6 levels found in serum and cerebrospinal fluid of patients with TSP and might have a significance in the immune pathogenesis of the disease.
1. Medizinische Klinik, Universität Mainz.
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Rott
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Fleischer
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Cash
D000818:Animals; D001921:Brain / Q000378:metabolism*; D003994:Bucladesine / Q000494:pharmacology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism*; D016355:Genes, pX; D015490:HTLV-I Infections / Q000378:metabolism*; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D014162:Transfection
D015850:Interleukin-6; D012333:RNA, Messenger; D003994:Bucladesine