Soluble tumor necrosis factor receptor inhibits interleukin 12 production by stimulated human adult microglial cells in vitro.

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.

Section: Discussionmentioning

confidence: 99%

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

Wang

Chen

Wandinger

et al. 2000

“…AMs produce both Th1 (IL-12) and Th2 (IL-10 and IL-13) cytokines (18,19) and secrete a panoply of mediators, including TNF, IL-1, IL-6, IL-8, and NO (19 -22). TNF plays a pivotal role in inflammation by stimulating inflammatory cells and increasing the production of cytokines such as IL-1, IL-6, IL-8, and IL-12 (22,23). Furthermore, there is some evidence suggesting an important role of TNF in the development of the Th1 response (24).…”

Section: Importance Of Histamine In the Cytokine Network In The Lung mentioning

confidence: 99%

Importance of Histamine in the Cytokine Network in the Lung Through H2 and H3 Receptors: Stimulation of IL-10 Production

Sirois

Ménard

Moses

et al. 2000

105

Histamine, a well-known inflammatory mediator, has been implicated in various immunoregulatory effects that are poorly understood. Thus, we tested the hypothesis that histamine inhibits the release of a proinflammatory cytokine, namely TNF, by stimulating the release of an anti-inflammatory cytokine, IL-10. Alveolar macrophages (AMs) from humans, Sprague Dawley rats, and the AM cell line, NR8383, were treated with different concentrations of histamine (10−5-10−7 M) for 2 h prior to their stimulation with suboptimal concentration of LPS (1 ng/ml) for 4 h. Histamine inhibited TNF release in a dose-dependent manner. This inhibition was mimicked by H2 and H3 receptor agonists, but not by H1 receptor agonist. Furthermore, we demonstrated the expression of H3 receptor mRNA in human AMs. Interestingly, treatment of AMs with anti-IL-10, anti-PGE2, or a NO synthase inhibitor (Nω-nitro-l-arginine methyl ester) before the addition of histamine abrogated the inhibitory effect of the latter on TNF release. Histamine treatment (10−5 M) increased the release of IL-10 from unstimulated (2.2-fold) and LPS-stimulated (1.7-fold) AMs. Unstimulated AMs, NR8383, express few copies of IL-10 mRNA, as tested by quantitative PCR, but expression of IL-10 was increased by 1.5-fold with histamine treatment. Moreover, the stimulation of IL-10 release by histamine was abrogated by pretreatment with anti-PGE2 or the NO synthase inhibitor, Nω-nitro-l-arginine methyl ester. Thus, histamine increases the synthesis and release of IL-10 from AMs through PGE2 and NO production. These results suggest that histamine may play an important role in the modulation of the cytokine network.

“…Besides being produced by CNS-infiltrating immune cells, IL-12 can be produced by neural cells including microglia (7)(8)(9)(10) and astrocytes (8,11). The demonstration of cerebral IL-12 induction in endotoxemic mice is particularly notable considering two studies that demonstrated that IL-12 unmasks latent autoimmune encephalitis in resistant mice and that microbial products, including LPS, can facilitate the induction of EAE by an IL-12-dependent pathway (12,13).…”

mentioning

confidence: 99%

Astrocyte-Targeted Expression of IL-12 Induces Active Cellular Immune Responses in the Central Nervous System and Modulates Experimental Allergic Encephalomyelitis

Pagenstecher¹,

Laßmann²,

Carson

et al. 2000

The role of IL-12 in the evolution of immunoinflammatory responses at a localized tissue level was investigated. Transgenic mice were developed with expression of either both the IL-12 subunits (p35 and p40) or only the IL-12 p40 subunit genes targeted to astrocytes in the mouse CNS. Glial fibrillary acidic protein (GF)-IL-12 mice, bigenic for the p35 and p40 genes, developed neurologic disease which correlated with the levels and sites of transgene-encoded IL-12 expression. In these mice, the brain contained numerous perivascular and parenchymal inflammatory lesions consisting of predominantly CD4+ and CD8+ T cells as well as NK cells. The majority of the infiltrating T cells had an activated phenotype (CD44high, CD45Rblow, CD62Llow, CD69high, VLA-4 high, and CD25+). Functional activation of the cellular immune response was also evident with marked cerebral expression of the IFN-γ, TNF, and IL-1αβ genes. Concomitant with leukocyte infiltration, the CNS expression of immune accessory molecules was induced or up-regulated, including ICAM-1, VCAM-1, and MHC class II and B7-2. Glial fibrillary acidic protein-p40 mice with expression of IL-12 p40 alone remained asymptomatic, with no inflammation evident at any age studied. The effect of local CNS production of IL-12 in the development of experimental autoimmune encephalomyelitis was studied. After immunization with myelin oligodendrocyte glycoprotein-peptides, GF-IL-12 mice had an earlier onset and higher incidence but not more severe disease. We conclude that localized expression of IL-12 by astrocytes can 1) promote the spontaneous development of activated type 1 T cell and NK cellular immunity and cytokine responses in the CNS, and 2) promote more effective Ag-specific T cell dynamics but not activity in experimental autoimmune encephalomyelitis.