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Trichostatin A Protects Liver against Septic Injury through Inhibiting Toll-Like Receptor Signaling.

Kim SJ, Park JS, Lee DW, Lee SM - Biomol Ther (Seoul) (2016)

Bottom Line: TSA improved sepsis-induced mortality, attenuated liver injury and decreased serum TNF-α and IL-6 levels.CLP increased nuclear translocation of nuclear factor kappa B and decreased cytosolic inhibitor of kappa B (IκB) protein expression, which were attenuated by TSA.Moreover, CLP decreased acetylation of IκB kinase (IKK) and increased association of IKK with IκB and TSA attenuated these alterations.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.

ABSTRACT
Sepsis, a serious clinical problem, is characterized by a systemic inflammatory response to infection and leads to organ failure. Toll-like receptor (TLR) signaling is intimately implicated in hyper-inflammatory responses and tissue injury during sepsis. Histone deacetylase (HDAC) inhibitors have been reported to exhibit anti-inflammatory properties. The aim of this study was to investigate the hepatoprotective mechanisms of trichostatin A (TSA), a HDAC inhibitor, associated with TLR signaling pathway during sepsis. The anti-inflammatory properties of TSA were assayed in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Polymicrobial sepsis was induced in mice by cecal ligation and puncture (CLP), a clinically relevant model of sepsis. The mice were intraperitoneally received TSA (1, 2 or 5 mg/kg) 30 min before CLP. The serum and liver samples were collected 6 and 24-h after CLP. TSA inhibited the increased production of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in LPS-stimulated RAW264.7 cells. TSA improved sepsis-induced mortality, attenuated liver injury and decreased serum TNF-α and IL-6 levels. CLP increased the levels of TLR4, TLR2 and myeloid differentiation primary response protein 88 (MyD88) protein expression and association of MyD88 with TLR4 and TLR2, which were attenuated by TSA. CLP increased nuclear translocation of nuclear factor kappa B and decreased cytosolic inhibitor of kappa B (IκB) protein expression, which were attenuated by TSA. Moreover, CLP decreased acetylation of IκB kinase (IKK) and increased association of IKK with IκB and TSA attenuated these alterations. Our findings suggest that TSA attenuates liver injury by inhibiting TLR-mediated inflammatory response during sepsis.

No MeSH data available.


Related in: MedlinePlus

Effect of TSA on serum levels and hepatic mRNA expressions of TNF-α and IL-6 in sepsis. Mice were intraperitoneally administered vehicle (normal saline) or 2 mg/kg TSA 30 min before CLP. The blood samples were collected from the inferior vena cava 6-h after CLP and then serum levels of TNF-α (A) and IL-6 (B) were determined. The liver tissues were collected 6-h after CLP and then hepatic mRNA expressions of TNF-α (C) and IL-6 (D) were determined. The results are presented as mean ± SEM (n=6-8 per group). *p<0.05, **p<0.01, ***p<0.001 versus sham group. †p<0.05, ††p<0.01 versus CLP group.
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f3-bt-24-387: Effect of TSA on serum levels and hepatic mRNA expressions of TNF-α and IL-6 in sepsis. Mice were intraperitoneally administered vehicle (normal saline) or 2 mg/kg TSA 30 min before CLP. The blood samples were collected from the inferior vena cava 6-h after CLP and then serum levels of TNF-α (A) and IL-6 (B) were determined. The liver tissues were collected 6-h after CLP and then hepatic mRNA expressions of TNF-α (C) and IL-6 (D) were determined. The results are presented as mean ± SEM (n=6-8 per group). *p<0.05, **p<0.01, ***p<0.001 versus sham group. †p<0.05, ††p<0.01 versus CLP group.

Mentions: The serum levels of TNF-α and IL-6 in the sham group were 186.0 ± 30.1 and 90.7 ± 3.2 pg/mL, respectively. CLP significantly increased TNF-α and IL-6 levels to 1.5- and 31.5-fold than those in the sham group, respectively, 6-h after CLP. These increases were attenuated by TSA (Fig. 3A, 3B). The hepatic TNF-α and IL-6 mRNA expression exhibited a marked increase to 2.8- and 1.5-fold than those in the sham group, respectively. Consistent with observation of serum cytokine levels, TSA attenuated the increases in TNF-α and IL-6 mRNA expression (Fig. 3C, 3D).


Trichostatin A Protects Liver against Septic Injury through Inhibiting Toll-Like Receptor Signaling.

Kim SJ, Park JS, Lee DW, Lee SM - Biomol Ther (Seoul) (2016)

Effect of TSA on serum levels and hepatic mRNA expressions of TNF-α and IL-6 in sepsis. Mice were intraperitoneally administered vehicle (normal saline) or 2 mg/kg TSA 30 min before CLP. The blood samples were collected from the inferior vena cava 6-h after CLP and then serum levels of TNF-α (A) and IL-6 (B) were determined. The liver tissues were collected 6-h after CLP and then hepatic mRNA expressions of TNF-α (C) and IL-6 (D) were determined. The results are presented as mean ± SEM (n=6-8 per group). *p<0.05, **p<0.01, ***p<0.001 versus sham group. †p<0.05, ††p<0.01 versus CLP group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4930282&req=5

f3-bt-24-387: Effect of TSA on serum levels and hepatic mRNA expressions of TNF-α and IL-6 in sepsis. Mice were intraperitoneally administered vehicle (normal saline) or 2 mg/kg TSA 30 min before CLP. The blood samples were collected from the inferior vena cava 6-h after CLP and then serum levels of TNF-α (A) and IL-6 (B) were determined. The liver tissues were collected 6-h after CLP and then hepatic mRNA expressions of TNF-α (C) and IL-6 (D) were determined. The results are presented as mean ± SEM (n=6-8 per group). *p<0.05, **p<0.01, ***p<0.001 versus sham group. †p<0.05, ††p<0.01 versus CLP group.
Mentions: The serum levels of TNF-α and IL-6 in the sham group were 186.0 ± 30.1 and 90.7 ± 3.2 pg/mL, respectively. CLP significantly increased TNF-α and IL-6 levels to 1.5- and 31.5-fold than those in the sham group, respectively, 6-h after CLP. These increases were attenuated by TSA (Fig. 3A, 3B). The hepatic TNF-α and IL-6 mRNA expression exhibited a marked increase to 2.8- and 1.5-fold than those in the sham group, respectively. Consistent with observation of serum cytokine levels, TSA attenuated the increases in TNF-α and IL-6 mRNA expression (Fig. 3C, 3D).

Bottom Line: TSA improved sepsis-induced mortality, attenuated liver injury and decreased serum TNF-α and IL-6 levels.CLP increased nuclear translocation of nuclear factor kappa B and decreased cytosolic inhibitor of kappa B (IκB) protein expression, which were attenuated by TSA.Moreover, CLP decreased acetylation of IκB kinase (IKK) and increased association of IKK with IκB and TSA attenuated these alterations.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.

ABSTRACT
Sepsis, a serious clinical problem, is characterized by a systemic inflammatory response to infection and leads to organ failure. Toll-like receptor (TLR) signaling is intimately implicated in hyper-inflammatory responses and tissue injury during sepsis. Histone deacetylase (HDAC) inhibitors have been reported to exhibit anti-inflammatory properties. The aim of this study was to investigate the hepatoprotective mechanisms of trichostatin A (TSA), a HDAC inhibitor, associated with TLR signaling pathway during sepsis. The anti-inflammatory properties of TSA were assayed in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Polymicrobial sepsis was induced in mice by cecal ligation and puncture (CLP), a clinically relevant model of sepsis. The mice were intraperitoneally received TSA (1, 2 or 5 mg/kg) 30 min before CLP. The serum and liver samples were collected 6 and 24-h after CLP. TSA inhibited the increased production of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in LPS-stimulated RAW264.7 cells. TSA improved sepsis-induced mortality, attenuated liver injury and decreased serum TNF-α and IL-6 levels. CLP increased the levels of TLR4, TLR2 and myeloid differentiation primary response protein 88 (MyD88) protein expression and association of MyD88 with TLR4 and TLR2, which were attenuated by TSA. CLP increased nuclear translocation of nuclear factor kappa B and decreased cytosolic inhibitor of kappa B (IκB) protein expression, which were attenuated by TSA. Moreover, CLP decreased acetylation of IκB kinase (IKK) and increased association of IKK with IκB and TSA attenuated these alterations. Our findings suggest that TSA attenuates liver injury by inhibiting TLR-mediated inflammatory response during sepsis.

No MeSH data available.


Related in: MedlinePlus