CEREBROSPINAL FLUID AND SERUM PROTEIN LEVELS OF TUMOUR NECROSIS FACTOR-ALPHA (TNF-α), INTERLEUKIN-6 (IL-6) AND SOLUBLE INTERLEUKIN-6 RECEPTOR (sIL-6R gp80) IN MULTIPLE SCLEROSIS PATIENTS

Vladić, Anton; Horvat, Gordana; Vukadin, Stjepan; Sučić, Zvonimir; Šimaga, Šumski

doi:10.1006/cyto.2002.1984

Cited by 56 publications

(43 citation statements)

References 18 publications

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“…Increased production of PGE 2 following peripheral inflammation has been reported in the CNS (32). The lack of significant up-regulation of TNF and IL-6 in CSF is in line with earlier data demonstrating low levels of these cytokines in CSF in general (33), and the discrepancy versus IL-1β levels further supports a possible separate regulation of the IL-1 system in RA CNS. Moreover, there were positive correlations between an increase in IL-1β and clinically defined fatigue, and the same positive trend was observed for sleep quality.…”

Section: Discussionsupporting

confidence: 85%

Peripheral inflammatory disease associated with centrally activated IL-1 system in humans and mice

Lampa

Westman

Kadetoff

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

138

103

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During peripheral immune activation caused by an infection or an inflammatory condition, the innate immune response signals to the brain and causes an up-regulation of central nervous system (CNS) cytokine production. Central actions of proinflammatory cytokines, in particular IL-1β, are pivotal for the induction of fever and fatigue. In the present study, the influence of peripheral chronic joint inflammatory disease in rheumatoid arthritis (RA) on CNS inflammation was investigated. Intrathecal interleukin (IL)-1β concentrations were markedly elevated in RA patients compared with controls or with patients with multiple sclerosis. Conversely, the anti-inflammatory IL-1 receptor antagonist and IL-4 were decreased in RA cerebrospinal fluid (CSF). Tumor necrosis factor and IL-6 levels in the CSF did not differ between patients and controls. Concerning IL-1β, CSF concentrations in RA patients were higher than in serum, indicating local production in the CNS, and there was a positive correlation between CSF IL-1β and fatigue assessments. Next, spinal inflammation in experimental arthritis was investigated. A marked increase of IL-1β, IL-18, and tumor necrosis factor, but not IL-6 mRNA production, in the spinal cord was observed, coinciding with increased arthritis scores in the KBxN serum transfer model. These data provide evidence that peripheral inflammation such as arthritis is associated with an immunological activation in the CNS in both humans and mice, suggesting a possible therapeutic target for centrally affecting conditions as fatigue in chronic inflammatory diseases, for which to date there are no specific treatments.

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Section: Discussionsupporting

confidence: 85%

Peripheral inflammatory disease associated with centrally activated IL-1 system in humans and mice

Lampa

Westman

Kadetoff

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

138

103

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“…The importance of this pleiotropic cytokine in inflammatory demyelination is underscored by its high expression in the CNS (42) and, specifically, in MS lesions at sites of active demyelination (43). IL-6 is also one of few cytokines unconditionally required for the development of experimental autoimmune encephalomyelitis, an animal model of MS (44).…”

Section: Discussionmentioning

confidence: 99%

TLR2 Stimulation Regulates the Balance between Regulatory T Cell and Th17 Function: A Novel Mechanism of Reduced Regulatory T Cell Function in Multiple Sclerosis

Nyirenda

Morandi

Vinkemeier

et al. 2015

The Journal of Immunology

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CD4+CD25hi FOXP3+ regulatory T cells (Tregs) maintain tolerance to self-Ags. Their defective function is involved in the pathogenesis of multiple sclerosis (MS), an inflammatory demyelinating disease of the CNS. However, the mechanisms of such defective function are poorly understood. Recently, we reported that stimulation of TLR2, which is preferentially expressed by human Tregs, reduces their suppressive function and skews them into a Th17-like phenotype. In this study, we tested the hypothesis that TLR2 activation is involved in reduced Treg function in MS. We found that Tregs from MS patients expressed higher levels of TLR2 compared with healthy controls, and stimulation with the synthetic lipopeptide Pam3Cys, an agonist of TLR1/2, reduced Treg function and induced Th17 skewing in MS patient samples more than in healthy controls. These data provide a novel mechanism underlying diminished Treg function in MS. Infections that activate TLR2 in vivo (specifically through TLR1/2 heterodimers) could shift the Treg/Th17 balance toward a proinflammatory state in MS, thereby promoting disease activity and progression.

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“…Myelin degeneration and axon remyelination failure in oligodendrocytes, which are associated with differentiation dysfunction, are pathological hallmarks of MS. Several lines of evidence indicate that TNF-a is one of the most relevant cytokines involved in the pathogenesis of this disease 7,8,[28][29][30] and mimics the effect of the disease on oligodendrocytes in vitro by promoting both cell death and impairment of the differentiation process. 12,31 In the present study, we confirmed that exposure to low concentrations of TNF-a (10 ng/ml) impairs OPC differentiation, causing an accumulation of early progenitors and reducing the relative amounts of differentiating oligodendrocytes in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…Evidence implicating TNF-a in the underlying pathology of MS includes: (i) reports that MS patients have elevated TNF-a levels at the sites of active MS lesions at autopsy, 7 (ii) reports that TNF-a levels are elevated in the cerebrospinal fluid and serum of individuals with MS compared with unaffected individuals and that these TNF-a levels correlate with the severity of the lesions. 8,9 Moreover, it has been widely reported that TNF-a is able to impair oligodendrocyte differentiation and that in leukemia cell lines, TNF-a-induced cell death requires impairments in the activity of mitochondrial respiratory chain complex I. Complex I is strategically important for regulating ATP synthesis and is one of the most important sources of reactive oxygen species (ROS) within cells.…”

mentioning

confidence: 99%

Tumor necrosis factor-α impairs oligodendroglial differentiation through a mitochondria-dependent process

et al. 2014

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Mitochondrial defects, affecting parameters such as mitochondrial number and shape, levels of respiratory chain complex components and markers of oxidative stress, have been associated with the appearance and progression of multiple sclerosis. Nevertheless, mitochondrial physiology has never been monitored during oligodendrocyte progenitor cell (OPC) differentiation, especially in OPCs challenged with proinflammatory cytokines. Here, we show that tumor necrosis factor alpha (TNF-a) inhibits OPC differentiation, accompanied by altered mitochondrial calcium uptake, mitochondrial membrane potential, and respiratory complex I activity as well as increased reactive oxygen species production. Treatment with a mitochondrial uncoupler (FCCP) to mimic mitochondrial impairment also causes cells to accumulate at the progenitor stage. Interestingly, AMP-activated protein kinase (AMPK) levels increase during TNF-a exposure and inhibit OPC differentiation. Overall, our data indicate that TNF-a induces metabolic changes, driven by mitochondrial impairment and AMPK activation, leading to the inhibition of OPC differentiation.

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CEREBROSPINAL FLUID AND SERUM PROTEIN LEVELS OF TUMOUR NECROSIS FACTOR-ALPHA (TNF-α), INTERLEUKIN-6 (IL-6) AND SOLUBLE INTERLEUKIN-6 RECEPTOR (sIL-6R gp80) IN MULTIPLE SCLEROSIS PATIENTS

Cited by 56 publications

References 18 publications

Peripheral inflammatory disease associated with centrally activated IL-1 system in humans and mice

Peripheral inflammatory disease associated with centrally activated IL-1 system in humans and mice

TLR2 Stimulation Regulates the Balance between Regulatory T Cell and Th17 Function: A Novel Mechanism of Reduced Regulatory T Cell Function in Multiple Sclerosis

Tumor necrosis factor-α impairs oligodendroglial differentiation through a mitochondria-dependent process

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