Modulation of Toll-Like Receptor 4 Expression on Human Monocytes by Tumor Necrosis Factor and Interleukin-6: Tumor Necrosis Factor Evokes Lipopolysaccharide Hyporesponsiveness, Whereas Interleukin-6 Enhances Lipopolysaccharide Activity

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Abstract
Toll-like receptors (TLR) play a pivotal role in the innate immune response, and the expression levels of these receptors may reflect the sensitivity of immune cells to infections. The binding of lipopolysaccharide (LPS) to TLR-4 triggers human monocytes to produce cytokines, which play a dominant role in the inflammatory response, as can be observed during sepsis and after polytrauma. Here, we evaluated TLR-4 expression of isolated monocytes in the presence of tumor necrosis factor (TNF)-alpha, interleukin (IL) 6, IL-8, and IL-10, and we investigated cellular activation of this treatment. TNF-alpha significantly down-regulated TLR-4 mRNA expression after 6 h (100% vs. 38.5% +/- 4%; P < 0.05). This down-regulation was followed by a dose- and time-dependent diminished expression of TLR-4 surface protein (100% vs. 8.0% +/- 5%; P < 0.01). Forty-eight hours after TNF-alpha treatment, a reduced nuclear factor (NF)-kappaB translocation and a diminished IL-6 secretion after LPS stimulation were found (100% vs. 42.0% +/- 23%; P < 0.05). In contrast, IL-6 incubation upregulated TLR-4 cell surface protein (100% vs. 165.8% +/- 24%; P < 0.05) and increased the ability to activate NF-kappaB and AP-1 after LPS stimulation. Stimulation with IL-8 or IL-10 had no significant effects. We conclude that not only LPS but also TNF-alpha and IL-6 have the potency to regulate the immune response via TLR-4. Down-regulation of TLR-4 by TNF-alpha is associated with LPS hyporeactivity for NF-kappaB formation, whereas upregulation of TLR-4 via IL-6 can increase the responsiveness of mononuclear phagocytes.