Dysregulation of cystathionine γ-lyase (CSE)/hydrogen sulfide pathway contributes to ox-LDL-induced inflammation in macrophage

Wang, Xianhui; Wang, Fen; You, Shoujiang; Cao, Yongjun; Cao, Li-dan; Han, Qiao; Liu, Chunfeng; Hu, Lifang

doi:10.1016/j.cellsig.2013.07.010

Cited by 101 publications

(78 citation statements)

References 32 publications

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“…As an endogenous enzyme, CSE is crucial to the generation of H 2 S. Previous studies have shown that CSE is involved in a variety of physiological and tumor processes (32)(33)(34), and the knockdown of CSE by shRNA can decrease cell proliferation, migration and tumor xenograft growth in nude mice (35). Consistent with this, the present data showed that the upregulation of the CSE protein in HepG2 cells overexpressing CXCL5 is positively associated with the proliferation and migration of HepG2 cells.…”

Section: Discussionsupporting

confidence: 79%

CXCL5 as an autocrine or paracrine cytokine is associated with proliferation and migration of hepatoblastoma HepG2 cells

et al. 2017

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Abstract. C-X-C motif chemokine ligand 5 (CXCL5) is a CXC-type chemokine that is a crucial inflammatory mediator and a powerful attractant for granulocytic immune cells. Increasing evidence has indicated that CXCL5 is involved in the tumorigenesis of various malignancies. The present investigation demonstrated that CXCL5 was expressed in both hepatoblastoma HepG2 cells and liver stellate LX-2 cells, and CXCL5's receptor C-X-C chemokine receptor type 2 (CXCR2) was expressed in HepG2 cells by reverse transcription-polymerase chain reaction (RT-PCR), western blotting and ELISA assays. Cell counting kit-8, colony formation and Transwell assays revealed that exogenous CXCL5 expression efficiently promoted proliferation, colony formation and migration of HepG2 cells. To explore the autocrine and paracrine roles of CXCL5 in the oncogenic potential of HepG2 cells, HepG2 cells overexpressing CXCL5 and LX-2 cells overexpressing CXCL5 were successfully constructed by gene transfection. Similarly, overexpression of CXCL5 in HepG2 also enhanced proliferation, colony formation and migration of HepG2 cells. Furthermore, the condition medium of LX-2 cells overexpressing CXCL5 affected the proliferation and migration of HepG2 cells. RT-PCR and western blotting assays were also conducted to explore whether overexpression of CXCL5 in HepG2 modulated the expression of genes. The results revealed that overexpression of CXCL5 regulated the expression of several genes, including N-myc downregulated gene 3,w B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein, P53, vascular endothelial growth factor, interleukin (IL)-18, IL-1β and cystathionine-γ-lyase. In conclusion, the present findings indicate that CXCL5/CXCR2 axis contributes to the oncogenic potential of hepatoblastoma via autocrine or paracrine pathways by regulating expression of genes associated with the progression of carcinoma. IntroductionHepatoblastoma (HB) is a prevalent malignancy among children, which histologically derives from pluripotent stem cells that may differentiate into liver cells and biliary epithelial cells, and accounts for almost two-thirds of pediatric malignant liver tumors (1,2). Although the survival rate of HB has increased from 35 to 75% during the last 30 years with the application of surgical excision, adjuvant chemotherapy and liver transplantation (3), additional investigation of the underlying molecular mechanism will be beneficial for the improving diagnosis and treatment of patients with HB.Previous studies have supported the hypothesis that the development of malignancies is closely associated with various cytokines, in which chemokines appear to have crucial roles. Chemokines are members of the cytokine super family and are secreted by various cell types, including immune, mesothelial, endometrial glandular and stromal cells, and trophoblasts (4). According to the order of conserved cysteine residues, chemokines are classified as C, CC, CXC and C (X) 3 C. Additionally, CXC chemokines are further grouped into ELR + CXC and ELR -CXC on the b...

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Section: Discussionsupporting

confidence: 79%

CXCL5 as an autocrine or paracrine cytokine is associated with proliferation and migration of hepatoblastoma HepG2 cells

et al. 2017

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“…Experimental evidence for an antiatherosclerotic effect of H 2 S has been obtained in numerous studies in hyperlipidemic animal and cell models (15,(24)(25)(26), but the antiatherosclerotic effect in the context of diabetes has not been previously investigated. Recent data published by our group demonstrated that treatment with H 2 S decreased aortic atherosclerotic plaque formation and partially restored aortic endothelium-dependent relaxation in ApoE 2/2 mice fed an HFD (15).…”

Section: Discussionmentioning

confidence: 99%

Hydrogen Sulfide Induces Keap1 S-sulfhydration and Suppresses Diabetes-Accelerated Atherosclerosis via Nrf2 Activation

et al. 2016

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Hydrogen sulfide (H2S) has been shown to have powerful antioxidative and anti-inflammatory properties that can regulate multiple cardiovascular functions. However, its precise role in diabetes-accelerated atherosclerosis remains unclear. We report here that H2S reduced aortic atherosclerotic plaque formation with reduction in superoxide (O2−) generation and the adhesion molecules in streptozotocin (STZ)-induced LDLr−/− mice but not in LDLr−/−Nrf2−/− mice. In vitro, H2S inhibited foam cell formation, decreased O2− generation, and increased nuclear factor erythroid 2–related factor 2 (Nrf2) nuclear translocation and consequently heme oxygenase 1 (HO-1) expression upregulation in high glucose (HG) plus oxidized LDL (ox-LDL)–treated primary peritoneal macrophages from wild-type but not Nrf2−/− mice. H2S also decreased O2− and adhesion molecule levels and increased Nrf2 nuclear translocation and HO-1 expression, which were suppressed by Nrf2 knockdown in HG/ox-LDL–treated endothelial cells. H2S increased S-sulfhydration of Keap1, induced Nrf2 dissociation from Keap1, enhanced Nrf2 nuclear translocation, and inhibited O2− generation, which were abrogated after Keap1 mutated at Cys151, but not Cys273, in endothelial cells. Collectively, H2S attenuates diabetes-accelerated atherosclerosis, which may be related to inhibition of oxidative stress via Keap1 sulfhydrylation at Cys151 to activate Nrf2 signaling. This may provide a novel therapeutic target to prevent atherosclerosis in the context of diabetes.

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“…This finding is consistent with previous findings because inflammation has been implicated as a critical mechanism responsible for the progressive nature of neurodegeneration (44,62), and there is an inverse link between an activated transsulfuration pathway and the immune response. In experimental models, H 2 S exerts antineuroinflammatory effects via inhibition of p38/Jun nuclear kinase and NF-κB signaling pathways (63), and the inhibition of CSE by PPG leads to increased inflammation (64). Furthermore, CSE has been shown to be a modulator of oxidative stress in mice (42).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Cystathionine γ-Lyase Suppresses Detrimental Effects of Spinocerebellar Ataxia Type 3

Snijder

Baratashvili

Grzeschik

et al. 2015

Mol Med

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Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine (polyQ) disorder caused by a CAG repeat expansion in the ataxin-3 (ATXN3) gene resulting in toxic protein aggregation. Inflammation and oxidative stress are considered secondary factors contributing to the progression of this neurodegenerative disease. There is no cure that halts or reverses the progressive neurodegeneration of SCA3. Here we show that overexpression of cystathionine γ-lyase, a central enzyme in cysteine metabolism, is protective in a Drosophila model for SCA3. SCA3 flies show eye degeneration, increased oxidative stress, insoluble protein aggregates, reduced levels of protein persulfidation and increased activation of the innate immune response. Overexpression of Drosophila cystathionine γ-lyase restores protein persulfidation, decreases oxidative stress, dampens the immune response and improves SCA3-associated tissue degeneration. Levels of insoluble protein aggregates are not altered; therefore, the data implicate a modifying role of cystathionine γ-lyase in ameliorating the downstream consequence of protein aggregation leading to protection against SCA3-induced tissue degeneration. The cystathionine γ-lyase expression is decreased in affected brain tissue of SCA3 patients, suggesting that enhancers of cystathionine γ-lyase expression or activity are attractive candidates for future therapies.

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Dysregulation of cystathionine γ-lyase (CSE)/hydrogen sulfide pathway contributes to ox-LDL-induced inflammation in macrophage

Cited by 101 publications

References 32 publications

CXCL5 as an autocrine or paracrine cytokine is associated with proliferation and migration of hepatoblastoma HepG2 cells

CXCL5 as an autocrine or paracrine cytokine is associated with proliferation and migration of hepatoblastoma HepG2 cells

Hydrogen Sulfide Induces Keap1 S-sulfhydration and Suppresses Diabetes-Accelerated Atherosclerosis via Nrf2 Activation

Overexpression of Cystathionine γ-Lyase Suppresses Detrimental Effects of Spinocerebellar Ataxia Type 3

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