TNF Production in Macrophages Is Genetically Determined and Regulates Inflammatory Disease in Rats

Gillett, Alan; Marta, Mónica; Jin, Tao; Tuncel, Jonatan; Leclerc, P.; Lange, Stefan; Holmdahl, Rikard; Olsson, Tomas; Harris, Robert A.; Jagodic, Maja

doi:10.4049/jimmunol.0904101

Cited by 14 publications

(9 citation statements)

References 64 publications

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“…In particular, TNFα plays a role in activating T cells and rejecting tumor cells [17–19] and IFNγ inhibits tumor growth and metastasis by activating NK cells as well as T lymphocytes [20,21]. The results of our study were remarkably consistent with previous studies.…”

Section: Resultssupporting

confidence: 91%

Study on the Immunomodulation Effect of Isodon japonicus Extract via Splenocyte Function and NK Anti-Tumor Activity

Hwang

Kim

Park

et al. 2012

IJMS

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Here we investigated the potential immune-enhancing activity of Isodon japonicus on murine splenocyte and natural-killer (NK) cells in vitro. The ethanol extract of I. japonicus significantly enhanced the proliferation of splenocyte and induced the significant enhancement of NK cells’ activity against tumor cells (YAC-1). In addition, I. japonicus increased the production of interferon (IFN)-γ and tumor necrosis factor (TNF)-α, suggesting that the increase in NK cell cytotoxicity could be due to the enhancement of the NK cell production of both cytokines. Taken together, I. japonicus extract inhibited the growth of human leukemia cells (K562) by 74%. Our observation indicated that the anti-tumor effects of I. japonicus may be attributed to its ability to serve as a stimulant of NK anti-tumor activity. In addition, our results support the development of functional food studies on I. japonicus.

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Section: Resultssupporting

confidence: 91%

Study on the Immunomodulation Effect of Isodon japonicus Extract via Splenocyte Function and NK Anti-Tumor Activity

Hwang

Kim

Park

et al. 2012

IJMS

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“…Disease was allowed to evolve to a clinical score of 1 when animals were randomized to receive placebo or 100 g/kg ShK-186 every other day (EOD). Clinical score is computed as according to Gillett et al (2010). Overall disease severity in the study was high.…”

Section: Discussionmentioning

confidence: 99%

Durable Pharmacological Responses from the Peptide ShK-186, a Specific Kv1.3 Channel Inhibitor That Suppresses T Cell Mediators of Autoimmune Disease

Tarcha

Chi

Muñoz‐Elías

et al. 2012

J Pharmacol Exp Ther

110

161

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The Kv1.3 channel is a recognized target for pharmaceutical development to treat autoimmune diseases and organ rejection. ShK-186, a specific peptide inhibitor of Kv1.3, has shown promise in animal models of multiple sclerosis and rheumatoid arthritis. Here, we describe the pharmacokinetic-pharmacodynamic relationship for ShK-186 in rats and monkeys. The pharmacokinetic profile of ShK-186 was evaluated with a validated high-performance liquid chromatography-tandem mass spectrometry method to measure the peptide's concentration in plasma. These results were compared with single-photon emission computed tomography/computed tomography data collected with an 111 In-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-conjugate of ShK-186 to assess whole-blood pharmacokinetic parameters as well as the peptide's absorption, distribution, and excretion. Analysis of these data support a model wherein ShK-186 is absorbed slowly from the injection site, resulting in blood concentrations above the Kv1.3 channelblocking IC 50 value for up to 7 days in monkeys. Pharmacodynamic studies on human peripheral blood mononuclear cells showed that brief exposure to ShK-186 resulted in sustained suppression of cytokine responses and may contribute to prolonged drug effects. In delayed-type hypersensitivity, chronic relapsing-remitting experimental autoimmune encephalomyelitis, and pristane-induced arthritis rat models, a single dose of ShK-186 every 2 to 5 days was as effective as daily administration. ShK-186's slow distribution from the injection site and its long residence time on the Kv1.3 channel contribute to the prolonged therapeutic effect of ShK-186 in animal models of autoimmune disease.

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“…Microarray data was obtained in the two inbred rat strains DA and PVG av1 as a first step to genetically dissect differences in pathway activation after experimental TBI. These strains have previously been extensively studied in autoimmune disease models such as EAE, a model of MS, which has provided both information on genetically regulated pathways as well as specific genes of importance for disease pathogenesis (5,13,29,31,44). Furthermore, the strains differ both in inflammatory response and neuronal survival in a standardized peripheral nerve injury model (19,22).…”

Section: Discussionmentioning

confidence: 99%

Naturally Occurring Variation in the Glutathione-S-Transferase 4 Gene Determines Neurodegeneration After Traumatic Brain Injury

Nimer

Ström²,

Lindblom³

et al. 2013

Antioxidants & Redox Signaling

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Aim: Genetic factors are important for outcome after traumatic brain injury (TBI), although exact knowledge of relevant genes/pathways is still lacking. We here used an unbiased approach to define differentially activated pathways between the inbred DA and PVG rat strains. The results prompted us to study further if a naturally occurring genetic variation in glutathione-S-transferase alpha 4 (Gsta4) affects the outcome after TBI. Results: Survival of neurons after experimental TBI is increased in PVG compared to the DA strain. Global expression profiling analysis shows the glutathione metabolism pathway to be the most regulated between the strains, with increased Gsta4 in PVG among top regulated transcripts. A congenic strain (R5) with a PVG genomic insert containing the Gsta4 gene on DA background displays a reversal of the strain pattern for Gsta4 expression and increased survival of neurons compared to DA. Gsta4 is known to effectively reduce 4-hydroxynonenal (4-HNE), a noxious by-product of lipid peroxidation. Immunostaining of 4-HNE was evident in both rat and human TBI. Intracerebral injection of 4-HNE resulted in neurodegeneration with increased levels of a marker for nerve injury in cerebrospinal fluid of DA compared to R5. Innovation: These findings provide strong support for the notion that the inherent capability of coping with increased 4-HNE after TBI affects outcome in terms of nerve cell loss. Conclusion: A naturally occurring variation in Gsta4 expression in rats affects neurodegeneration after TBI. Further studies are needed to explore if genetic variability in Gsta4 can be associated to outcome also in human TBI. Antioxid. Redox Signal. 18, 784-794.

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TNF Production in Macrophages Is Genetically Determined and Regulates Inflammatory Disease in Rats

Abstract: Material

Cited by 14 publications

References 64 publications

Study on the Immunomodulation Effect of Isodon japonicus Extract via Splenocyte Function and NK Anti-Tumor Activity

Study on the Immunomodulation Effect of Isodon japonicus Extract via Splenocyte Function and NK Anti-Tumor Activity

Durable Pharmacological Responses from the Peptide ShK-186, a Specific Kv1.3 Channel Inhibitor That Suppresses T Cell Mediators of Autoimmune Disease

Naturally Occurring Variation in the Glutathione-S-Transferase 4 Gene Determines Neurodegeneration After Traumatic Brain Injury

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