Opposite effects of IFN beta on cytokine homeostasis in LPS- and T cell contact-activated human monocytes.

Multiple sclerosis (MS) is an immune-mediated disease improved by interferon-beta (IFNbeta) therapy. IFNbeta may owe its anti-inflammatory property to its ability to induce interleukin-1 receptor antagonist (IL-1Ra) without triggering IL-1beta synthesis in human monocytes. Furthermore, we recently demonstrated that IFNbeta inhibits the production of IL-1beta and tumor necrosis factor-alpha (TNF) in human monocytes activated by cellular contact with stimulated T cells, a mechanism which we suspected of playing an important part in the pathogenesis of chronic inflammatory diseases including MS. Here we compare modulatory effects of IFNbeta on the production of proinflammatory cytokines (IL-1beta, IL-1alpha, TNF, and IL-6) and IL-1Ra in human monocytes stimulated by lipopolysaccharides (LPS) and isolated plasma membranes of stimulated T cells (msHUT), which are likely to reflect monocyte activation in acute and chronic inflammation, respectively. In monocytes activated by either LPS or msHUT, IFNbeta did not modulate the secretion of IL-1alpha and IL-6, but it enhanced the production of IL-1Ra in a dose-dependent manner. However, in monocytes activated by msHUT, the expression of cell-associated and intracellular IL-1alpha was inhibited by IFNbeta, correlating with the inhibition of IL-1alpha transcript. IFNbeta inhibited the expression (mRNA) and production (protein) of IL-1beta and TNF, while enhancing those of IL-1Ra in monocytes activated by msHUT. In contrast, in monocytes activated by LPS, IFNbeta enhanced the expression and production of IL-1beta, TNF, and IL-1Ra, suggesting that it did not display anti-inflammatory properties in these conditions. This study demonstrates that IFNbeta displays opposite effects depending on the type of activation of human monocytes, suggesting that it may affect different pathogenic mechanisms in opposite ways.