title: The Anti-Inflammatory Effect and Intestinal Barrier Protection of HU210 Differentially Depend on TLR4 Signaling in Dextran Sulfate Sodium-Induced Murine Colitis.
abstract: Ulcerative colitis (UC) is strongly associated with inflammation and intestinal barrier disorder. The nonselective cannabinoid receptor agonist HU210 has been shown to ameliorate inflamed colon in colitis, but its effects on intestinal barrier function and extraintestinal inflammation are unclear.
  
  
  
  To investigate the effects and the underlying mechanism of HU210 action on the UC in relation to a role of TLR4 and MAP kinase signaling.
  
  
  
  Wild-type (WT) and TLR4 knockout (Tlr4-/-) mice were exposed to 4% dextran sulfate sodium (DSS) for 7 days. The effects of HU210 on inflammation and intestinal barrier were explored.
  
  
  
  Upon DSS challenge, mice suffered from bloody stool, colon shortening, intestinal mucosa edema, pro-inflammatory cytokine increase and intestinal barrier destruction with goblet cell depletion, increased intestinal microflora accompanied with elevated plasma lipopolysaccharide, reduced mRNA expression of the intestinal tight junction proteins, and abnormal ratio of CD4+/CD8+T cells in the intestinal Peyer's patches. Pro-inflammatory cytokines in the plasma and the lung, as well as pulmonary myeloperoxidase activity, indicators of extraintestinal inflammation were increased. Protein expression of p38α and pp38 was up-regulated in the colon of WT mice. Tlr4-/-mice showed milder colitis. HU210 reversed the intestinal barrier changes in both strains of mice, but alleviated inflammation only in WT mice.
  
  
  
  Our study indicates that in experimental colitis, HU210 displays a protective effect on the intestinal barrier function independently of the TLR4 signaling pathway; however, in the extraintestinal tissues, the anti-inflammatory action seems through affecting TLR4-mediated p38 mitogen-activated protein kinase pathway.
authors.affiliation: Department of Pathophysiology, Institute of Digestive Disease, Tongji University School of Medicine, Siping Road 1239, Shanghai, 200092, China.
authors.forename: Sisi
authors.initials: S
authors.lastname: Lin
authors.affiliation: Department of Pathophysiology, Institute of Digestive Disease, Tongji University School of Medicine, Siping Road 1239, Shanghai, 200092, China. liyongyu@tongji.edu.cn.
authors.forename: Yongyu
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Immunology and Pathogenic Biology, Tongji University School of Medicine, Siping Road 1239, Shanghai, 200092, China.
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Pathophysiology, Institute of Digestive Disease, Tongji University School of Medicine, Siping Road 1239, Shanghai, 200092, China.
authors.forename: Ruiqin
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Pathophysiology, Institute of Digestive Disease, Tongji University School of Medicine, Siping Road 1239, Shanghai, 200092, China.
authors.forename: Lizhi
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Physiology, Zunyi Medical and Pharmaceutical College, Zunyi, 563000, China.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Pathophysiology, Institute of Digestive Disease, Tongji University School of Medicine, Siping Road 1239, Shanghai, 200092, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland.
authors.forename: Jakub
authors.initials: J
authors.lastname: Fichna
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D003092:Colitis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D003106:Colon / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000276:immunology; D016264:Dextran Sulfate / Q000633:toxicity; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D000069196:Gastrointestinal Microbiome / Q000187:drug effects; D020397:Goblet Cells / Q000187:drug effects / Q000473:pathology; D007249:Inflammation; D008168:Lung / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048308:Mitogen-Activated Protein Kinase 14 / Q000187:drug effects / Q000378:metabolism; D010539:Permeability; D009195:Peroxidase / Q000378:metabolism; D010581:Peyer's Patches / Q000276:immunology / Q000473:pathology; D010750:Phosphoproteins; D062725:Tight Junction Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000187:drug effects* / Q000235:genetics / Q000276:immunology
chemical_list: D016207:Cytokines; D018691:Excitatory Amino Acid Antagonists; D010750:Phosphoproteins; D062725:Tight Junction Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D013759:Dronabinol; D016264:Dextran Sulfate; D009195:Peroxidase; D048308:Mitogen-Activated Protein Kinase 14; C062018:HU 211
keywords: HU210; Intestinal barrier function; Toll-like receptor 4; Ulcerative colitis; p38 mitogen-activated protein kinase