Thioredoxin suppresses 1-methyl-4-phenylpyridinium-induced neurotoxicity in rat PC12 cells

Abstract. Interleukin (IL)-6 has been shown to protect neuronal cells from cell death induced by various stimulants. Although neuronal cells including PC12 cells were shown to produce IL-6, little is known about the effects of dopaminergic neurotoxins, 1,2,3,4-tetrahydroisoquinoline (TIQ) and 1-methyl-4-phenylpyridinium ion (MPP + ), on IL-6 expression in PC12 cells. In the present study, we investigated the role of IL-6 in the TIQ-and MPP + -induced cell death in PC12 cells. Treatment with 3.2 mM TIQ for 24 h caused a delayed cell death (lactate dehydrogenase (LDH) leakage and nuclear DNA fragmentation) markedly 72 h after the addition. Addition of 0.4 mM MPP + caused LDH leakage and nuclear DNA fragmentation 24 h after the addition. The cell death induced by MPP + was inhibited by an inhibitor of caspases, z-Val-Ala-Asp(OMe)-fluoromethylketone. The cell death induced by TIQ or MPP + was inhibited by nerve growth factor and 10% serum and significantly enhanced by the treatment with anti-IL-6 antibody. Both neurotoxins decreased the IL-6 mRNA level in PC12 cells without changing the other tested mRNA levels (IL-1a , b-actin, etc.). These findings suggest that dopaminergic neurotoxins cause cell death in PC12 cells at least partially by changing IL-6 expression.

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“…2A), as described previously (5,24). The addition of 0.2 mM MPP + slightly but not significantly induced LDH leakage.…”

Section: Cell Death Induced By Tiq or Mppmentioning

confidence: 75%

Possible Role of Interleukin-6 in PC12 Cell Death Induced by MPP+ and Tetrahydroisoquinoline

et al. 2003

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“…The LDH activity in culture supernatants was measured, as previously described (23), after the cells were treated with 50 M H 2 O 2 for 1, 3, or 6 h.…”

Section: Lactate Dehydrogenase (Ldh) Activity Assaymentioning

confidence: 99%

Redox-Sensing Release of Human Thioredoxin from T Lymphocytes with Negative Feedback Loops

Kondo

Ishii

Kwon

et al. 2004

The Journal of Immunology

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106

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Thioredoxin (TRX) is released from various types of mammalian cells despite no typical secretory signal sequence. We show here that a redox-active site in TRX is essential for its release from T lymphocytes in response to H2O2 and extracellular TRX regulates its own H2O2-induced release. Human T cell leukemia virus type I-transformed T lymphocytes constitutively release a large amount of TRX. The level of TRX release is augmented upon the addition of H2O2, but suppressed upon the addition of N-acetylcysteine. In the culture supernatant of a Jurkat transfectant expressing the tagged TRX-wild type (WT), the tagged TRX protein is rapidly released at 1 h and kept at a constant level until 6 h after the addition of H2O2. In contrast, another type of transfectant expressing the tagged TRX mutant (C32S/C35S; CS) fails to release the protein. H2O2-induced release of TRX from the transfectant is inhibited by the presence of rTRX-WT in a dose-dependent manner. Preincubation of the transfectant with rTRX-WT for 1 h at 37°C, but not 0°C, results in a significant suppression of the TRX release, reactive oxygen species, and caspase-3 activity induced by H2O2, respectively. Confocal microscopy and Western blot analysis show that extracellular rTRX-WT added to the culture does not obviously enter T lymphocytes until 24 h. These results collectively suggest that the oxidative stress-induced TRX release from T lymphocytes depends on a redox-sensitive event and may be regulated by negative feedback loops using reactive oxygen species-mediated signal transductions.

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“…However, other studies reported that endogenous PGs are not involved in the action of GGA (Bilski et al, 1988); therefore, the molecular mechanism of the cytoprotective action of GGA is not fully understood. Recent information suggests that GGA increases Trx (Hirota et al, 2000;Dekigai et al, 2001;Bai et al, 2002) and Hsp expression (Hirakawa et al, 1996) in various cells and exerts cytoprotection.…”

Section: Introductionmentioning

confidence: 99%

Cytoprotective Effects of Geranylgeranylacetone against Retinal Photooxidative Damage

Tanito¹,

Kwon²,

Kondo³

et al. 2005

J. Neurosci.

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Exposure to excessive light induces retinal photoreceptor cell damage, leading to development and progression of various retinal diseases. We tested the effect of geranylgeranylacetone (GGA), an acyclic polyisoprenoid, on light-induced retinal damage in mice. Oral treatment with GGA (1.0 mg/d) for 5 d induced thioredoxin (Trx) and heat shock protein 72 (Hsp72) predominantly in the retinal pigment epithelium (RPE). After white light exposure (8000 lux for 2 h), the percentage of terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling-positive photoreceptor cells decreased significantly at 24 and 96 h, and the number of photoreceptor cell nuclei at 96 h and the electroretinographic amplitudes of the a- and b-waves at 4 and 10 d increased significantly in GGA-pretreated mice compared with saline-pretreated mice. Light-induced upregulations of 8-hydroxy-2-deoxyguanosine and 4-hydroxy-2-nonenal-modified protein, markers of oxidative stress, were inhibited by GGA pretreatment. To elucidate the cytoprotective mechanism of GGA and Trx, we used human K-1034 RPE cells and mouse photoreceptor-derived 661W cells. In K-1034 cells, GGA (10 μm) induced intracellular Trx, Hsp72, and extracellular Trx but not extracellular Hsp72. Extracellular Trx (0.75 nm) attenuated H2O2(200 μm)-induced cell damage in 661W cells. Pretreatment with GGA and overexpression of Trx in K-1034 cells counteracted H2O2(50 μm)-induced attenuation of cellular latex bead incorporation. Protection of phagocytotic activity through induction of Trx and possibly Hsp72 in RPE cells and elimination of oxidative stress in the photoreceptor layer through release of Trx from RPE cells may be mechanisms of GGA-mediated cytoprotection. Therefore, Trx is a neurotrophic factor released from RPE cells and plays a crucial role in maintaining photoreceptor cell integrity.

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Thioredoxin suppresses 1-methyl-4-phenylpyridinium-induced neurotoxicity in rat PC12 cells

Cited by 70 publications

References 18 publications

Possible Role of Interleukin-6 in PC12 Cell Death Induced by MPP+ and Tetrahydroisoquinoline

Possible Role of Interleukin-6 in PC12 Cell Death Induced by MPP+ and Tetrahydroisoquinoline

Redox-Sensing Release of Human Thioredoxin from T Lymphocytes with Negative Feedback Loops

Cytoprotective Effects of Geranylgeranylacetone against Retinal Photooxidative Damage

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