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The Anti-Inflammatory Effect and Intestinal Barrier Protection of HU210 Differentially Depend on TLR4 Signaling in Dextran Sulfate Sodium-Induced Murine Colitis.
Dig Dis Sci. 2017 02; 62(2):372-386.DD

Abstract

BACKGROUND

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.

AIMS

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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+Show Affiliations

Department of Pathophysiology, Institute of Digestive Disease, Tongji University School of Medicine, Siping Road 1239, Shanghai, 200092, China.Department of Pathophysiology, Institute of Digestive Disease, Tongji University School of Medicine, Siping Road 1239, Shanghai, 200092, China. liyongyu@tongji.edu.cn.Department of Immunology and Pathogenic Biology, Tongji University School of Medicine, Siping Road 1239, Shanghai, 200092, China.Department of Pathophysiology, Institute of Digestive Disease, Tongji University School of Medicine, Siping Road 1239, Shanghai, 200092, China.Department of Pathophysiology, Institute of Digestive Disease, Tongji University School of Medicine, Siping Road 1239, Shanghai, 200092, China.Department of Physiology, Zunyi Medical and Pharmaceutical College, Zunyi, 563000, China.Department of Pathophysiology, Institute of Digestive Disease, Tongji University School of Medicine, Siping Road 1239, Shanghai, 200092, China.Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27995407

Citation

Lin, Sisi, et al. "The Anti-Inflammatory Effect and Intestinal Barrier Protection of HU210 Differentially Depend On TLR4 Signaling in Dextran Sulfate Sodium-Induced Murine Colitis." Digestive Diseases and Sciences, vol. 62, no. 2, 2017, pp. 372-386.
Lin S, Li Y, Shen L, et al. The Anti-Inflammatory Effect and Intestinal Barrier Protection of HU210 Differentially Depend on TLR4 Signaling in Dextran Sulfate Sodium-Induced Murine Colitis. Dig Dis Sci. 2017;62(2):372-386.
Lin, S., Li, Y., Shen, L., Zhang, R., Yang, L., Li, M., Li, K., & Fichna, J. (2017). The Anti-Inflammatory Effect and Intestinal Barrier Protection of HU210 Differentially Depend on TLR4 Signaling in Dextran Sulfate Sodium-Induced Murine Colitis. Digestive Diseases and Sciences, 62(2), 372-386. https://doi.org/10.1007/s10620-016-4404-y
Lin S, et al. The Anti-Inflammatory Effect and Intestinal Barrier Protection of HU210 Differentially Depend On TLR4 Signaling in Dextran Sulfate Sodium-Induced Murine Colitis. Dig Dis Sci. 2017;62(2):372-386. PubMed PMID: 27995407.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The Anti-Inflammatory Effect and Intestinal Barrier Protection of HU210 Differentially Depend on TLR4 Signaling in Dextran Sulfate Sodium-Induced Murine Colitis. AU - Lin,Sisi, AU - Li,Yongyu, AU - Shen,Li, AU - Zhang,Ruiqin, AU - Yang,Lizhi, AU - Li,Min, AU - Li,Kun, AU - Fichna,Jakub, Y1 - 2016/12/19/ PY - 2016/05/24/received PY - 2016/11/30/accepted PY - 2016/12/21/pubmed PY - 2017/7/14/medline PY - 2016/12/21/entrez KW - HU210 KW - Intestinal barrier function KW - Toll-like receptor 4 KW - Ulcerative colitis KW - p38 mitogen-activated protein kinase SP - 372 EP - 386 JF - Digestive diseases and sciences JO - Dig. Dis. Sci. VL - 62 IS - 2 N2 - BACKGROUND: 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. AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. SN - 1573-2568 UR - https://www.unboundmedicine.com/medline/citation/27995407/The_Anti_Inflammatory_Effect_and_Intestinal_Barrier_Protection_of_HU210_Differentially_Depend_on_TLR4_Signaling_in_Dextran_Sulfate_Sodium_Induced_Murine_Colitis_ L2 - https://doi.org/10.1007/s10620-016-4404-y DB - PRIME DP - Unbound Medicine ER -