HDAC2 is required by the physiological concentration of glucocorticoid to inhibit inflammation in cardiac fibroblasts.

We previously suggested that endogenous glucocorticoids (GCs) may inhibit myocardial inflammation induced by lipopolysaccharide (LPS) in vivo. However, the possible cellular and molecular mechanisms were poorly understood. In this study, we investigated the role of physiological concentration of GCs in inflammation induced by LPS in cardiac fibroblasts and explored the possible mechanisms. The results showed that hydrocortisone at the dose of 127 ng/mL (equivalent to endogenous basal level of GCs) inhibited LPS (100 ng/mL)-induced productions of TNF-α and IL-1ß in cardiac fibroblasts. Xanthine oxidase/xanthine (XO/X) system impaired the anti-inflammatory action of GCs through downregulating HDAC2 activity and expression. Knockdown of HDAC2 restrained the anti-inflammatory effects of physiological level of hydrocortisone, and blunted the ability of XO/X system to downregulate the inhibitory action of physiological level of hydrocortisone on cytokines. These results suggested that HDAC2 was required by the physiological concentration of GC to inhibit inflammatory response. The dysfunction of HDAC2 induced by oxidative stress might be account for GC resistance and chronic inflammatory disorders during the cardiac diseases.

Tissue Transglutaminase-Regulated Transformed Growth Factor-ß1 in the Parasite Links Schistosoma japonicum Infection with Liver Fibrosis.

Transforming growth factor (TGF-ß1) is among the strongest factors of liver fibrogenesis, but its association with Schistosoma-caused liver fibrosis is controversial. Tissue transglutaminase (tTG) is the principal enzyme controlling TGF-ß1 maturation and contributes to Sj-infected liver fibrosis. Here we aim to explore the consistency between tTG and TGF-ß1 and TGF-ß1 source and its correlation with liver fibrosis after Sj-infection. TGF-ß1 was upregulated at weeks 6 and 8 upon liver fibrosis induction. During tTG inhibition, TGF-ß1 level decreased in sera and liver of infected mice. TGF-ß1 showed positive staining in liver containing Sj adult worms and eggs. TGF-ß1 was also detected in Sj adult worm sections, soluble egg antigen and Sj adult worm antigen, and adult worms' culture medium. The TGF-ß1 mature peptide cDNA sequence and its extended sequence were amplified through RT-PCR and RACE-PCR using adult worms as template, and sequence is analyzed and loaded to NCBI GenBank (number GQ338152.1). TGF-ß1 transcript in Sj eggs was higher than in adult worms. In Sj-infected liver, transcriptional level of TGF-ß1 from Sj, but not mouse liver, correlated with liver fibrosis extent. This study provides evidence that tTG regulates TGF-ß1 and illustrates the importance of targeting tTG in treating Sj infection-induced fibrosis.

Involvement of IL-13 and tissue transglutaminase in liver granuloma and fibrosis after schistosoma japonicum infection.

Schistosomiasis, one of the most devastating parasitic diseases, is caused by Schistosoma japonicum (Sj) infection resulting in serious liver fibrosis. Interleukin- (IL-) 13, which is produced by TH2 cells, is a critical profibrotic cytokine found in various organs, including the liver. Tissue transglutaminase (tTG), a group of multifunctional enzymes, serves a central function in the pathogenesis of chronic liver diseases. However, the relationship between IL-13, tTG, and liver fibrosis during Schistosoma infection has not been established. This study investigated the involvement of IL-13 and tTG in liver fibrogenesis during Sj infection in mice. Five weeks after Sj infection, granuloma and fibrosis development in the liver coincided with an increase in IL-13 and tTG in the liver and the upregulation of serum IL-13 in infected mice. Administration of cystamine, an inhibitor of tTG, abrogated the increase in both tTG and IL-13 in infected mice and ameliorated liver fibrogenesis and granuloma development. This result establishes a novel link among IL-13, tTG, and liver granuloma and fibrosis under Sj infection. Based on their important functions in liver fibrosis induced by Sj infection, IL-13 and tTG could be promising potential drug targets against schistosomiasis.