lipoteichoic-acid and Fibrosis

Topics: Actins; Animals; Cell Line; Cell Wall; Disease Models, Animal; Female; Fibroblasts; Fibrosis; Hot Temperature; Humans; Lactobacillus; Lipopolysaccharides; Male; Matrix Metalloproteinase 1; Mice, Inbred BALB C; Probiotics; Signal Transduction; Skin; Smad Proteins; Tail; Teichoic Acids; Transforming Growth Factor beta; Wound Healing

We previously reported the finding that pancreatic stellate cells (PSCs) have a phagocytic function. The aim of the present study was to investigate whether engulfment of gram-positive bacteria by PSCs plays any role in the pathogenesis of pancreatic fibrosis.. Rat PSCs were cultured with lipoteichoic acid (LTA) or bacteria and analyzed for α-smooth muscle actin expression and collagen secretion. Human pancreata were obtained from routine autopsies of 20 cases; a diagnosis of gram-positive sepsis was made in 10 of the cases (sepsis group), but sepsis had not been diagnosed in the other 10 cases (control group). Pancreatic tissue was stained with anti-LTA antibody, and the severity of pancreatic fibrosis was evaluated by histological scoring.. Bacteria and LTA were internalized into the cytoplasm of cultured PSCs. Exposure to LTA or bacteria significantly increased α-smooth muscle actin expression and collagen secretion. Blockade of toll-like receptor 2 significantly inhibited the increase in collagen secretion in response to LTA. There was no significant difference in the severity of pancreatic fibrosis between the sepsis group and the control group.. The fibrogenic action of PSCs seems to be more strongly associated with activation of the toll-like receptor-dependent pathway than it is with phagocytosis of bacteria by PSCs.

Topics: Animals; Cells, Cultured; Fibrosis; Gram-Positive Bacteria; Lipopolysaccharides; Male; Pancreas; Pancreatic Stellate Cells; Phagocytosis; Rats; Rats, Wistar; Teichoic Acids; Toll-Like Receptor 2

Autoimmune disorder and associated multifocal organ inflammations such as dry gland syndrome are occasionally observed; however, their etiologies are not clearly understood. We previously reported that chronic colitis-harboring TCR alpha(-/-) x AIM(-/-) mice show primary biliary cirrhosis (PBC)-like bile duct damage in the liver. Gram-positive bacterial infection is one of the candidates for the pathogenesis of PBC. We also reported that the bacterial cell wall component lipoteichoic acid (LTA) was detected at the sites of inflammation around damaged bile ducts in PBC patients. On the basis of these facts, we hypothesized that LTA might affect the pathogenesis of bile duct damage in the livers of TCR alpha(-/-) x AIM(-/-) mice. LTA was detected not only in the portal area with inflammation in the liver but also throughout the gastrointestinal tract, from the stomach to the colon, and especially in the epithelium at sites of inflammation. In addition, LTA was detected around both pancreatic ducts with inflammation and at the distal renal tubules with inflammation in TCR alpha(-/-) x AIM(-/-) mice. Furthermore, in the liver, pancreas, kidney, and colon, fibrous stroma were detected at the sites of LTA-positive inflammation foci. Bacterial LTA might affect the pathogenesis of epithelial inflammation followed by fibrosis in systemic multifocal epithelial inflammations in chronic colitis-harboring TCR alpha(-/-) x AIM(-/-) mice with PBC-like bile duct damage.

Topics: Animals; Apoptosis Regulatory Proteins; Colitis; Epithelium; Fibrosis; Inflammation; Lipopolysaccharides; Liver Cirrhosis, Biliary; Mice; Mice, Knockout; Receptors, Antigen, T-Cell, alpha-beta; Receptors, Immunologic; Receptors, Scavenger; Teichoic Acids

Gram-positive bacterial products such as peptidoglycan (PGN) and lipoteichoic acid (LTA) are potent stimulators of innate inflammatory responses. We previously reported that lipopolysaccharide (LPS), a major biologically active agent of gram-negative bacteria, induces a proinflammatory response via the Toll-like receptor (TLR) 4 in hepatic stellate cells (HSCs). Here we investigated the mechanism of proinflammatory action by PGN and LTA in activated human HSCs. Following treatment with either TNF-alpha or IL-1beta, expression of TLR2 and CD14 was determined by real-time PCR and Western blotting. NF-kappaB activation was assessed by NF-kappaB-driven luciferase assay and electrophoretic mobility shift assay. Interleukin-8 (IL-8) from culture supernatant was measured by ELISA. Activated human HSCs express TLR2 and CD14, which are receptors for PGN and LTA signaling. TNF-alpha and IL-1beta significantly upregulated the expression of TLR2 mRNA and protein in HSCs. PGN and LTA induced NF-kappaB activation and stimulated production of IL-8 in HSCs. Pretreatment with TNF-alpha or IL-1beta augmented NF-kappaB activation and IL-8 production in response to PGN or LTA. Both PGN- and LTA-induced NF-kappaB activation and IL-8 secretion were completely inhibited by anti-TLR2 blocking antibody (T2.5). These findings suggest that TNF-alpha or IL-1beta primed HSCs enhance the production of IL-8 in response to PGN and LTA through augmentation of the TLR2 system.

Topics: Adenoviridae; Biomarkers; Cell Culture Techniques; Cell Line, Transformed; Cytokines; Fibrosis; Genes, Reporter; Hepatocytes; Humans; Inflammation; Interleukin-1; Interleukin-8; Lipopolysaccharide Receptors; Lipopolysaccharides; Liver; Luciferases; NF-kappa B; Peptidoglycan; Teichoic Acids; Toll-Like Receptor 2; Tumor Necrosis Factor-alpha; Up-Regulation