title: Hyaluronic acid fragments evoke Kupffer cells via TLR4 signaling pathway.
abstract: Kupffer cells, expressing toll-like receptor 4 (TLR4), play a central role in hepatic ischemia/reperfusion (I/R) injury. Hyaluronic acid (HA) fragments, degradative products of high-molecular-weight HA (HMW-HA), acquire the ability to activate immune cells under inflammatory conditions. Here we investigated whether HA fragments could activate Kupffer cells and analyzed the underlying mechanism. Kupffer cells were isolated from wild-type mice (WT, C3H/HeN) and TLR4 mutant mice (C3H/HeJ) and HA fragments were produced by the methods of enzyme digestion and chromatography. Then Kupffer cells were stimulated by HA fragments or other control stimuli. The activation of Kupffer cells was estimated as the release of pro-inflammatory cytokines. The activation of p38 MAPK pathway of Kupffer cells was checked and blocking experiments were done as well. The results indicated that HA fragments acquired the ability to activate Kupffer cells in vitro, which was TLR4 dependent and not due to contamination of lipopolysaccharide. Experiments of p38 MAPK kinase inhibition by SB-203580 verified p38 MAPK was required in HA fragments induced Kupffer cells activation. This suggests that HA fragments, degradative products of one of the major glycosaminoglycans of the extracellular matrix, play critical roles in Kupffer cell activation mediated by TLR4 signaling pathway, which is, at least partially, dependent on p38 MAPK activation.
authors.affiliation: Department of Emergency Surgery, Union Hospital Affiliated to Huazhong University of Science and Technology, Wuhan, 430022, China. camelzjx@yahoo.com.cn
authors.forename: JinXiang
authors.initials: J
authors.lastname: Zhang
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Qing
authors.initials: Q
authors.lastname: Xiao
authors.forename: HuiFang
authors.initials: H
authors.lastname: Liang
authors.forename: ZhuoYa
authors.initials: Z
authors.lastname: Li
authors.forename: ChunFang
authors.initials: C
authors.lastname: Jiang
authors.forename: HeShui
authors.initials: H
authors.lastname: Wu
authors.forename: QiChang
authors.initials: Q
authors.lastname: Zheng
mesh_terms: D000818:Animals; D004789:Enzyme Activation; D006820:Hyaluronic Acid / Q000494:pharmacology*; D007728:Kupffer Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D051197:Toll-Like Receptor 4; D006820:Hyaluronic Acid; D048051:p38 Mitogen-Activated Protein Kinases