Contribution of tissue transglutaminase to the severity of hepatic fibrosis resulting from Schistosoma japonicum infection through the regulation of IL-33/ST2 expression.

BACKGROUND: Tissue transglutaminase (tTG)-regulating IL-13 plays an important role in the pathogenesis of liver fibrosis resulting from Schistosoma japonicum (Sj) infection. IL-33 and its receptor ST2 are involved in Th2-biased immune responses through the release of IL-5 and IL-13 and subsequent hepatic granuloma pathology induced by Sj infection. However, the relationship between tTG, IL-33/ST2, and liver fibrosis during Schistosoma infection has not been established. RESULTS: This study investigated the link between tTG and IL-33/ST2 in the induction of liver fibrogenesis during Sj infection in mice. The extent of liver fibrosis coincided with an increase in tTG and IL-33/ST2 expression in the liver of infected mice between five to eight weeks, with a peak of correlation at six weeks after Sj infection. The inhibition of tTG activity through cystamine administration or gene knockout alleviated the level of TLR4, NF-κB pathway molecules, IL-33/ST2, and the severity of liver fibrosis resulting from Sj infection. CONCLUSIONS: These results indicate that during Sj infection tTG may control liver fibrosis at least partially through TLR4, NF-κB pathway activation and then IL-33/ST2. tTG, IL-33 or ST2 might be promising drug targets against liver fibrosis induced by Sj infection.

Positive Feedback Regulation between Transglutaminase 2 and Toll-Like Receptor 4 Signaling in Hepatic Stellate Cells Correlates with Liver Fibrosis Post Schistosoma japonicum Infection.

Liver fibrosis induced by Schistosoma japonicum (Sj) infection is characterized by the accumulation of extracellular matrix (ECM). The activated and differentiated hepatic stellate cells (HSCs) are the predominant ECM-producing cell type in the liver. Toll-like receptor (TLR) 4 pathway activation plays a key role in mice liver fibrosis models induced by alcohol, biliary ligation, and carbon tetrachloride 4. In this work, we found that TLR4 pathway activation correlated with the severity of liver fibrosis post Sj infection. The TLR4 receptor inhibitor TAK242 reduced the extent of liver fibrosis. The increased expression of TLR4, α-smooth muscle actin (α-SMA), and cytoglobin was observed in the HSCs of mouse liver after Sj infection. In response to stimulation with either lipopolysaccharide or Sj's soluble egg antigen (SEA), high levels of TLR4 and α-SMA were induced in HSCs and were inhibited by TAK242 treatment. In previous work, we had reported that a high level of transglutaminase 2 (TGM2) is crucial for liver fibrosis post Sj infection. Herein, we found that TLR4 signaling also controlled Tgm2 expression. Inhibition of TGM2 activity by cystamine (CTM) in Sj-infected mice or in HSCs induced with all-trans-retinoic acid (ATRA) stimulation led to a lowered activation of TLR4 signaling and a reduced α-SMA expression. These results were confirmed by downregulating the Tgm2 gene by specific siRNA. These observations implied the presence of a positive feedback regulation between TGM2 and TLR4 signaling in HSCs that correlated with liver fibrosis post Sj infection. This novel connection between TGM2 and TLR4 pathway activation in liver fibrosis induced by Sj infection enhances our understanding of liver diseases.

Effect of cigarette smoking and alcohol consumption on disease activity and physical functioning in ankylosing spondylitis: a cross-sectional study.

The effect of cigarette smoking and alcohol consumption on the disease activity and physical functioning in ankylosing spondylitis (AS) is currently understated. Present study aims to investigate the relationship between them. A total of 425 patients with AS were recruited in the study and their smoking and drinking habit were investigated with a semi-quantitative food frequency questionnaire. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), and Metrology Index (BASMI) were evaluated. Parameters including fingertip-to-floor distance, overall assessment of health, nocturnal pain, total back pain and morning stiffness were analyzed as well. Blood erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were determined. For 118 (27.8%) AS patients with smoking habit, the scorings of BASDAI, BASFI, BASMI and other physical parameters (including fingertip-to-floor, overall assessment of health, nocturnal pain and total back pain) were higher than those in patients without smoking. 101 (23.8%) AS patients with alcohol consumption demonstrated significantly higher scores in BASMI (P < 0.05). In hierarchical multiple regression analysis, the cigarette smoking and alcohol consumption variables contributed to the variance in BASDAI scores, adding an additional 1.6% to the overall R-square, resulting in a final R-square of 5.1%. Smoking has a negative effect on disease activity of patients with AS and the patients' physical functioning. Alcohol consumption would aggravate the overall physical functioning of AS patient. The results indicated the potential benefit of quitting smoking and drinking for AS patients.