IFN-β-1b Inhibits IL-12 Production in Peripheral Blood Mononuclear Cells in an IL-10-Dependent Mechanism: Relevance to IFN-β-1b Therapeutic Effects in Multiple Sclerosis

Abstract

IL-12 is a proinflammatory cytokine secreted by dendritic cells in response to microbial Ags and mitogens. IL-12 is thought to contribute to the pathogenesis of autoimmune diseases such as multiple sclerosis (MS). This is based on studies in experimental allergic encephalomyelitis and the demonstration that PBMC IL-12 production correlates with disease progression in MS. IFN-β-1b is an effective treatment for MS, which is thought to involve in part inhibition of proinflammatory cytokines. In this study we examined the effect of in vitro treatment with IFN-β-1b, on mitogen-induced IL-12 production in human PBMC and myelin basic protein-specific T cell lines obtained from healthy donors and MS patients. We demonstrate that IFN-β-1b significantly inhibits inducible IL-12 p40 up to 80% and biologically active IL-12 p70 up to 70% beginning at a dose of 10 IU/ml. This inhibition is IL-10 dependent, as it could be blocked by anti-IL-10 but not anti-IL-4 or control Abs. Thus, endogenously produced IL-10 is a required cofactor for the IFN-β-1b inhibitory effect on IL-12 to occur. We conclude that IFN-β-1b has a profound inhibitory effect on PBMC IL-12 production in vitro, and that this effect is IL-10 dependent. These findings are potentially relevant to the therapeutic mechanism of IFN-β-1b in MS.

Altered phenotype and function of blood dendritic cells in multiple sclerosis are modulated by IFN-βand IL-10

“…Correspondingly, IFN-g production by MNCs was significantly reduced by DCs pretreated with IL-10 1 IFN-b . Together with the results by Wang et al [22] that endogenous production of IL-10 is a required cofactor for the IFN-b -1b inhibitory effect on IL-12, the present findings suggest that effects obtained by IFN-b and IL-10 in combination on DCs in vitro could provide a novel mechanism to manipulate DCs in a desirable way in MS.…”

“…The concentration of 1000 U/ml of IFN-b is 5±10 fold higher than the concentration achieved in the circulation by current treatment of MS with IFN-b -1b [20]. The concentration of 1000 U/ml has, however, been shown to inhibit IL-12 production by DCs [15] and to modulate functionally important molecules on DCs [21], and is widely used for in vitro studies [22]. DCs from both MS patients and healthy controls showed strong allostimulatory capacity in allogeneic MLR (Fig.…”

Regulatory Effect of IFN-κ, A Novel Type I IFN, On Cytokine Production by Cells of the Innate Immune System

“…In virally infected mice, endogenously expressed IFN-␣␤ inhibited the ability of LPS to induce IL-12, while neutralization of IFN-␣␤ enhanced IL-12 and IFN-␥ production (34). Lastly, Wang et al (35) demonstrated that IFN-␤ inhibits IL-12 production in Staphylococcus aureus Cowan-plus IFN-␥-stimulated human PBMC in an IL-10-dependent mechanism. In this study, the authors did not observe enhancement by IFN-␤ of basal IL-10 production in monocytes and suggested that the IFN-␤ effect was mediated by inhibition of IFN-␥ priming.…”

Cytokine changes during interferon-beta therapy in multiple sclerosis: Correlations with interferon dose and MRI response

“…IFN-β has been shown to decrease clinical and MRI measures of disease activity in MS (Interferon Beta Study Group 1993, Paty et al, 1993,PRISMS 1998,Simon et al, 1999. IFN-β acts to increase IL-10 levels and reduce IL-12 levels in MS patients, thus improving the ratio of IL-10 to IL-12 (Correale et al, 1995,Rudick et al, 1996,Wang et al, 2000,Byrnes et al, 2002, Berghella et al, 2005, Ersoy et al, 2005. The mechanism of IL-12 suppression has been shown to depend on IL-10 induction (Wang et al, 2000).…”

“…IFN-β acts to increase IL-10 levels and reduce IL-12 levels in MS patients, thus improving the ratio of IL-10 to IL-12 (Correale et al, 1995,Rudick et al, 1996,Wang et al, 2000,Byrnes et al, 2002, Berghella et al, 2005, Ersoy et al, 2005. The mechanism of IL-12 suppression has been shown to depend on IL-10 induction (Wang et al, 2000). Increased CSF IL-10 levels during IFN-β treatment correlate with clinical response to therapy (Rudick et al, 1998).…”