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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 TLR signaling pathway in septic liver. Mice were intraperitoneally administered vehicle or 2 mg/kg TSA 30 min before CLP. The liver tissues were collected 6-h after CLP and then TLR4 (A), TLR2 (B), MyD88 (C) and TRIF (D) protein expression were determined. Liver lysates were immunoprecipitated with anti-TLR4 and anti-TLR2 antibodies and precipitated proteins were immunoblotted using anti-MyD88 (E–F) and anti-TRIF (G) antibodies. 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 versus CLP group.
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f5-bt-24-387: Effect of TSA on TLR signaling pathway in septic liver. Mice were intraperitoneally administered vehicle or 2 mg/kg TSA 30 min before CLP. The liver tissues were collected 6-h after CLP and then TLR4 (A), TLR2 (B), MyD88 (C) and TRIF (D) protein expression were determined. Liver lysates were immunoprecipitated with anti-TLR4 and anti-TLR2 antibodies and precipitated proteins were immunoblotted using anti-MyD88 (E–F) and anti-TRIF (G) antibodies. 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 versus CLP group.

Mentions: To determine the effect of TSA on TLR signaling pathway, we first determined the TLR4 and TLR2 protein expression. CLP significantly increased TLR4 and TLR2 protein expression to 1.9- and 1.8-fold, respectively, than those in the sham group 6-h after CLP. These increases were attenuated by TSA (Fig. 5A, 5B). CLP significantly increased MyD88 and TRIF protein expression to 1.7- and 1.5-fold, respectively, than those in the sham group 6-h after CLP. TSA attenuated increase in MyD88 protein expression, not TRIF (Fig. 5C, 5D). CLP significantly increased association of MyD88 with TLR4 and TLR2 to 1.5- and 1.6-fold than those in the sham group, respectively. These increases were attenuated by TSA (Fig. 5E, 5F). CLP significantly increased association of TRIF with TLR4 to 1.8-fold than that in the sham group. TSA did not affect this increase (Fig. 5G).


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 TLR signaling pathway in septic liver. Mice were intraperitoneally administered vehicle or 2 mg/kg TSA 30 min before CLP. The liver tissues were collected 6-h after CLP and then TLR4 (A), TLR2 (B), MyD88 (C) and TRIF (D) protein expression were determined. Liver lysates were immunoprecipitated with anti-TLR4 and anti-TLR2 antibodies and precipitated proteins were immunoblotted using anti-MyD88 (E–F) and anti-TRIF (G) antibodies. 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 versus CLP group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5-bt-24-387: Effect of TSA on TLR signaling pathway in septic liver. Mice were intraperitoneally administered vehicle or 2 mg/kg TSA 30 min before CLP. The liver tissues were collected 6-h after CLP and then TLR4 (A), TLR2 (B), MyD88 (C) and TRIF (D) protein expression were determined. Liver lysates were immunoprecipitated with anti-TLR4 and anti-TLR2 antibodies and precipitated proteins were immunoblotted using anti-MyD88 (E–F) and anti-TRIF (G) antibodies. 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 versus CLP group.
Mentions: To determine the effect of TSA on TLR signaling pathway, we first determined the TLR4 and TLR2 protein expression. CLP significantly increased TLR4 and TLR2 protein expression to 1.9- and 1.8-fold, respectively, than those in the sham group 6-h after CLP. These increases were attenuated by TSA (Fig. 5A, 5B). CLP significantly increased MyD88 and TRIF protein expression to 1.7- and 1.5-fold, respectively, than those in the sham group 6-h after CLP. TSA attenuated increase in MyD88 protein expression, not TRIF (Fig. 5C, 5D). CLP significantly increased association of MyD88 with TLR4 and TLR2 to 1.5- and 1.6-fold than those in the sham group, respectively. These increases were attenuated by TSA (Fig. 5E, 5F). CLP significantly increased association of TRIF with TLR4 to 1.8-fold than that in the sham group. TSA did not affect this increase (Fig. 5G).

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