Interleukin-12: Amiss in MS

Karp, Christopher L.

doi:10.1002/1531-8249(199906)45:6<689::aid-ana1>3.0.co;2-m

Cited by 17 publications

(9 citation statements)

References 52 publications

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“…The proinflammatory cytokines produced by immune cells determine the final outcome of the disease (11)(12)(13)(14). Using the EAE model of MS, we have shown earlier that in vivo treatment with lisofylline or tyrphostin inhibits the pathogenesis of CNS inflammation and demyelination in active immunization and adoptive transfer models of EAE in SJL/J mice (30,31).…”

Section: Discussionmentioning

confidence: 99%

“…IL-12 is a 70-kDa heterodimeric proinflammatory cytokine, produced mainly by macrophage/microglial cells in the CNS, that plays a critical role in the differentiation of encephalitogenic Th1 cells and pathogenesis of EAE and MS (12)(13)(14). MS patients showed increased expression of IL-12 in brain lesions, cerebrospinal fluid, and circulation in association with clinical relapses (15)(16)(17)(18)(19)(20).…”

Section: Ultiple Sclerosis (Ms)mentioning

confidence: 99%

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Curcumin Inhibits Experimental Allergic Encephalomyelitis by Blocking IL-12 Signaling Through Janus Kinase-STAT Pathway in T Lymphocytes

Natarajan

Bright

2002

The Journal of Immunology

268

169

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Experimental allergic encephalomyelitis (EAE) is a CD4+ Th1 cell-mediated inflammatory demyelinating autoimmune disease of the CNS that serves as an animal model for multiple sclerosis (MS). IL-12 is a proinflammatory cytokine that plays a crucial role in the induction of neural Ag-specific Th1 differentiation and pathogenesis of CNS demyelination in EAE and MS. Curcumin (1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is a naturally occurring polyphenolic phytochemical isolated from the rhizome of the medicinal plant Curcuma longa. It has profound anti-inflammatory activity and been traditionally used to treat inflammatory disorders. In this study we have examined the effect and mechanism of action of curcumin on the pathogenesis of CNS demyelination in EAE. In vivo treatment of SJL/J mice with curcumin significantly reduced the duration and clinical severity of active immunization and adoptive transfer EAE. Curcumin inhibited EAE in association with a decrease in IL-12 production from macrophage/microglial cells and differentiation of neural Ag-specific Th1 cells. In vitro treatment of activated T cells with curcumin inhibited IL-12-induced tyrosine phosphorylation of Janus kinase 2, tyrosine kinase 2, and STAT3 and STAT4 transcription factors. The inhibition of Janus kinase-STAT pathway by curcumin resulted in a decrease in IL-12-induced T cell proliferation and Th1 differentiation. These findings highlight the fact that curcumin inhibits EAE by blocking IL-12 signaling in T cells and suggest its use in the treatment of MS and other Th1 cell-mediated inflammatory diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Ultiple Sclerosis (Ms)mentioning

confidence: 99%

Curcumin Inhibits Experimental Allergic Encephalomyelitis by Blocking IL-12 Signaling Through Janus Kinase-STAT Pathway in T Lymphocytes

Natarajan

Bright

2002

The Journal of Immunology

268

169

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“…Nevertheless, the findings presented here have important, testable therapeutic implications. While suppression of IL-12 is likely a primary mechanism of action of therapeutic IFN-g in multiple sclerosis [4,54], IFN-+ is known to be counterproductive in this disease [55]. Thus, more specific targeting of IL-12 production or responsiveness in multiple sclerosis might be expected to lead to greater therapeutic efficacy.…”

Section: Discussionmentioning

confidence: 99%

Type I interferons and IL-12: convergence and cross-regulation among mediators of cellular immunity

Byrnes

Cuomo

et al. 2001

Eur. J. Immunol.

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Therapeutic use of type I IFN (IFN- § / g ) has become common. Many of the diverse diseases targeted are marked by pathogenetic abnormalities in cell-mediated immunity (CMI), these cellular immune responses either causing injury to the host, lacking sufficient vigor for virus or tumor clearance, or both. In general, therapeutic efficacy is limited. It is thus notable that the pleiotropic effects of type I IFN on CMI remain poorly understood. We characterized the effects of type I IFN on the production of IL-12, the central immunoregulatory cytokine of the CD4 + T cell arm of CMI. We show that type I IFN are potent inhibitors of IL-12 production by human monocytes/macrophages. The underlying mechanism involves transcriptional inhibition of the IL-12p40 gene, marked by down-regulation of PU.1 binding activity at the upstream Ets site of the IL-12p40 promoter. Type I IFN have previously been shown to be able to substitute for IL-12 in driving IFN-+ production from T and NK cells. The ability of IFN- § / g to suppress IL-12 production while up-regulating IFN-+ production suggests a possible mechanistic basis for the difficulties of employing these cytokines in diseases involving abnormalities of CMI.

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“…Further, our novel finding of a negative correlation between the percentage of circulating CD4 + CXCR3 + Th1 cells and the plasma levels of Th2-related cytokine IL-10, along with a report showing decreased IL-10 mRNA levels in association with MS relapse [33], suggest substantial roles for such cells in the pathogenesis of MS [23]. On the other hand, their inverse relationship to IL-12p70 levels found in the present study seems to be paradoxical, as IL-12 is critical for the development of Th1 responses [12] and IL-12p40 mRNA levels have been shown to be increased during active stages of MS [33]. However, our finding might be attributed to the consumption of this biologically active form (p70) of IL-12 in the systemic circulation due to the persistent Th1 immune deviation.…”

Section: Discussionmentioning

confidence: 99%

Differences in systemic and central nervous system cellular immunity relevant to relapsing–remitting multiple sclerosis

et al. 2005

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In order to elucidate the differences between systemic and central nervous system (CNS) immunity that are relevant to exacerbations of multiple sclerosis (MS), paired peripheral blood and cerebrospinal fluid (CSF) samples obtained from 36 non-treated patients with relapsing-remitting MS (RRMS) were simultaneously examined using flow cytometry to determine the percentages of functional lymphocyte subsets, as well as enzyme-linked immunosorbent assays for measuring soluble immune mediators. Active RRMS patients (n = 27) were characterized by an increase in CD4+ CXCR3+ Th1 cells in blood as compared with inactive patients (n = 9), and this parameter was inversely correlated with plasma levels of IL-10 and IL- 12p70. In contrast, an increase in the percentage of CD4+ CD25+ cells and a decrease in the percentage of CD8+ CD11a(high) cells were features of CSF samples from those with active RRMS. Further, CSF CD4+ CD25+ cells had a close association with leukocyte counts as well as albumin and CXCL10 levels in the CSF, and, thus, could be useful as a measure for inflammatory reactions in the CNS. On the other hand, CD8+ CD11a(high) cells may function as immunoregulatory cells, as their percentage in the CSF showed a positive correlation with CSF levels of the anti-inflammatory cytokine IL-4. These findings suggest that MS relapses occur in a combination with altered cell-mediated immunity that differs between the peripheral blood and CSF compartments, while measurement of lymphocyte subsets may be helpful for monitoring disease status.

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Interleukin-12: Amiss in MS

Cited by 17 publications

References 52 publications

Curcumin Inhibits Experimental Allergic Encephalomyelitis by Blocking IL-12 Signaling Through Janus Kinase-STAT Pathway in T Lymphocytes

Curcumin Inhibits Experimental Allergic Encephalomyelitis by Blocking IL-12 Signaling Through Janus Kinase-STAT Pathway in T Lymphocytes

Type I interferons and IL-12: convergence and cross-regulation among mediators of cellular immunity

Differences in systemic and central nervous system cellular immunity relevant to relapsing–remitting multiple sclerosis

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