Multiple Levels of Regulation of the Interleukin-6 System in Stroke

Acalovschi, Daniela; Wiest, T.; Hartmann, Marius; Farahmi, Maryam; Mansmann, Ulrich; Auffarth, Gerd U.; Grau, Armin J.; Green, Fiona R.; Grond‐Ginsbach, Caspar; Schwaninger, Markus

doi:10.1161/01.str.0000079815.38626.44

Cited by 128 publications

(109 citation statements)

References 25 publications

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“…However, our findings are supported by recent evidence that energy expenditure and body temperature are lower in the À174 CC genotype in healthy male and female subjects. 14,31 Altogether, this indicates that our finding is not coincidental although further studies are needed to investigate if these results can be applied to random samples of a population. It also remains to be investigated whether the effect of the À174 G/ C genotype on overweight risk is confined to certain populations.…”

Section: Discussionmentioning

confidence: 62%

“…The À174 C allele seems to be associated with lower IL-6 transcription in different cell systems. 11,12,14 There is also clear evidence from experimental studies that endogenous IL-6 suppresses body fat mass and prevents late-onset obesity. 6 We and others have also reported that IL-6 stimulates energy expenditure in both experimental animals 6,26 and in humans.…”

Section: Discussionmentioning

confidence: 99%

“…10 The biallelic À174 IL-6 G/C SNP, which is located within the negative regulative domain of the IL-6 gene promoter, has been found to affect transcriptional regulation. Several studies of the biological relevance of the À174 G/C SNP have indicated that the most common À174 Ccontaining haplotypes are weaker enhancers of IL-6 transcription than those containing the À174 G. [11][12][13][14] Moreover, it has recently been reported that also the C allele of the À572 IL-6 G/C SNP is a stronger enhancer of IL-6 transcription. 15 Based on these findings, we hypothesized that low IL-6 gene transcription, caused by the À174 C or the À572 G alleles, could contribute to obesity in humans.…”

Section: Introductionmentioning

confidence: 99%

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A common polymorphism in the interleukin-6 gene promoter is associated with overweight

et al. 2004

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OBJECTIVE:Human body fat mass is to a large extent genetically determined, but little is known about the susceptibility genes for common obesity. Interleukin-6 (IL-6) suppresses body fat mass in rodents, and IL-6 treatment increases energy expenditure in both rodents and humans. The À174 G/C single-nucleotide polymorphism (SNP) in the IL-6 gene promoter is common in many populations, and À174 C-containing promoters have been found to be weaker enhancers of transcription. Moreover, a SNP at position À572 in the IL-6 promoter has recently been reported to affect transcription. The objective was to investigate the association between the IL-6 gene promoter SNPs and obesity. DESIGN: Trans-sectional association study of IL-6 gene promoter SNPs and indices of obesity. SUBJECTS: Two study populations, the larger one consisting of hypertensive individuals (mean age 57 y, 73% males, n ¼ 485) and the other consisting of 20 y younger nonobese healthy females (n ¼ 74). MEASUREMENTS: Genotyping for the À174 IL-6 G/C and the À572 G/C SNPs, body mass index (BMI), serum leptin levels, serum IL-6 levels, C-reactive protein, fasting blood glucose and various blood lipids. RESULTS: The common À174 C allele (f C ¼ 0.46), but not any À572 allele, was associated with higher BMI and higher serum leptin levels in both study populations. In the larger population, there were significant odds ratios for the association of CC (2.13) and GC (1.76) genotypes with overweight (BMI425 kg/m 2 ). Moreover, as the C allele was common, it accounted for a significant population-attributable risk of overweight (12%; CI 2-21%), although its average effect was modest in this sample. CONCLUSION: Genetically determined individual differences in production of IL-6 may be relevant for the regulation of body fat mass.

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Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A common polymorphism in the interleukin-6 gene promoter is associated with overweight

et al. 2004

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“…28,43,44 Furthermore, polymorphisms of the promoter IL-6 gene have been associated with stroke 45,46 and the IL-6 system has been associated with acute inflammatory response after stroke. 47 In addition, the IL-8 chemokine has also been associated with the recruitment of inflammatory cells and is increased in stroke patients. 48,49 It has been associated with amplification of the secondary inflammatory process following stroke.…”

Section: Resultsmentioning

confidence: 99%

The etiology of poststroke depression: a review of the literature and a new hypothesis involving inflammatory cytokines

et al. 2006

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Although poststroke depression is unlikely to represent a single disorder and numerous etiologies for different kinds of poststroke depression will likely emerge as the result of future research, we believe that a number of poststroke depressive disorders are likely to be the result of specific changes in brain pathology and neurophysiology. Nevertheless, there are relatively few hypotheses about the pathophysiology of poststroke depression. This paper, therefore, proposes a new hypothesis for poststroke depression involving increased production of proinflammatory cytokines resulting from brain ischemia in cerebral areas linked to the pathogenesis of mood disorders. This paper reviews the evidence supporting the hypothesis that proinflammatory cytokines are involved in the occurrence of stroke as well as mood disorders linked to the brain damage. The increased production of proinflammatory cytokines such as IL-1b, TNF-a or IL-18 resulting from stroke may lead to an amplification of the inflammatory process, particularly in limbic areas, and widespread activation of indoleamine 2,3-dioxygenase (IDO) and subsequently to depletion of serotonin in paralimbic regions such as the ventral lateral frontal cortex, polar temporal cortex and basal ganglia. The resultant physiological dysfunction may lead to poststroke depression. Future investigations may explore this hypothesis through more extensive studies on the role of proinflammatory cytokines, such as IL-1b, TNF-a or even IL-18, in patients with poststroke depression. Molecular Psychiatry (2006) 11, 984-991.

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“…Association with body temperature and infarct volume Parallel with FNG and TNF-a Acalovschi et al (2003) 48 ( Association with infarct volume and prognosis CRP, C-reactive protein; CSF, cerebrospinal fluid; FNG, fibrinogen; IL-1b, interleukin 1b; IL-1ra, interleukin-1 receptor antagonist; TNF-a, tumor necrosis factor-a; WBC, white blood cell.…”

Section: Serum Interleukin-6 In Stroke Patientsmentioning

confidence: 99%

Ambivalent Aspects of Interleukin-6 in Cerebral Ischemia: Inflammatory versus Neurotrophic Aspects

Suzuki

Tanaka

Suzuki

2008

J Cereb Blood Flow Metab

213

177

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Interleukin-6 (IL-6) is pleiotropic cytokine involved in many central nervous system disorders including stroke, and elevated serum IL-6 has been found in acute stroke patients. IL-6 is implicated in the inflammation, which contributes to both injury and repair process after cerebral ischemia. However, IL-6 is one of the neurotrophic cytokines sharing a common receptor subunit, gp130, with other neurotrophic cytokines, such as leukemia inhibitory factor (LIF) and ciliary neurotrophic factor. The expression of IL-6 is most prominently identified in neurons in the peri-ischemic regions, and LIF expression shows a similar pattern. The direct injection of these cytokines into the brain after ischemia can reduce ischemic brain injury. The cytokine receptors are localized on the neuron surface, suggesting that neurons are the cytokine target. The major IL-6 downstream signaling pathway is JAK-STAT, and Stat3 activation occurs mainly in neurons during postischemic reperfusion. Further investigation is necessary to clarify the exact role of Stat3 signaling in neuroprotection. Taken together, the information suggests that IL-6 plays a double role in cerebral ischemia, as an inflammatory mediator during the acute phase and as a neurotrophic mediator between the subacute and prolonged phases.

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Multiple Levels of Regulation of the Interleukin-6 System in Stroke

Cited by 128 publications

References 25 publications

A common polymorphism in the interleukin-6 gene promoter is associated with overweight

A common polymorphism in the interleukin-6 gene promoter is associated with overweight

The etiology of poststroke depression: a review of the literature and a new hypothesis involving inflammatory cytokines

Ambivalent Aspects of Interleukin-6 in Cerebral Ischemia: Inflammatory versus Neurotrophic Aspects

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