Bioactive hyaluronic acid fragments inhibit lipopolysaccharide-induced inflammatory responses via the Toll-like receptor
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RESEARCH ARTICLE
Bioactive hyaluronic acid fragments inhibit lipopolysaccharideinduced inflammatory responses via the Toll-like receptor 4 signaling pathway ✉)5, Maorong Wang (✉)6
Na You1,*, Sasa Chu2,*, Binggang Cai3, Youfang Gao1, Mizhou Hui4, Jin Zhu ( 1
Department of Infectious Disease, The People’s Hospital of Bozhou, Bozhou 236800, China; 2Department of Infectious Disease, The People’s Hospital of Linyi, Linyi 276000, China; 3Department of Infectious Disease, The People’s Hospital of Yancheng, Yancheng 224000, China; 4AnRuipu Biological Products Research Co., Ltd., Hangzhou 310019, China; 5Huadong Medical Institute of Biotechniques, Nanjing 210002, China; 6Institute of Liver Disease, Jinling Hospital, Nanjing 210002, China
© Higher Education Press 2020
Abstract The high- and the low-molecular weight hyaluronic acids (HMW-HA and LMW-HA, respectively) showed different biological activities in inflammation. However, the role of LMW-HA in inflammatory response is controversial. In this study, we aimed to investigate the effect of bioactive hyaluronan (B-HA) on lipopolysaccharide (LPS)-induced inflammatory responses in human macrophages and mice. B-HA was produced from HA treated with glycosylated recombinant human hyaluronidase PH20. Human THP-1 cells were induced to differentiate into macrophages. THP-1-derived macrophages were treated with B-HA, LPS, or B-HA + LPS. The mRNA expression and the production of inflammatory cytokines were determined using quantitative real-time PCR and enzyme-linked immunosorbent assay. The phosphorylation levels of proteins in the nuclear factor-kB (NF-kB), mitogen-activated protein kinase (MAPK), and IRF-3 signaling pathways were measured using Western blot. The in vivo efficacy of B-HA was assessed in a mouse model of LPS-induced inflammation. Results showed that B-HA inhibited the expression of TNF-α, IL-6, IL-1, and IFN-β, and enhanced the expression of the antiinflammatory cytokine IL-10 in LPS-induced inflammatory responses in THP-1-derived macrophages and in vivo. B-HA significantly suppressed the phosphorylation of the TLR4 signaling pathway proteins p65, IKKα/β, IkBα, JNK1/2, ERK1/2, p38, and IRF-3. In conclusion, our results demonstrated that the B-HA attenuated the LPSstimulated inflammatory response by inhibiting the activation of the TLR4 signaling pathway. B-HA could be a potential anti-inflammatory drug in the treatment of inflammatory disease. Keywords
bioactive hyaluronan; lipopolysaccharide; inflammatory cytokines; TLR4; human macrophages
Introduction Hyaluronic acid (HA), a negatively charged polymer with repeated units of β-(1,4)-D-glucuronic acid–β-(1,3)-Nacetyl-D-glucosamine, is a nonprotein extracellular molecule secreted by many cell types [1,2]. HA is abundant in a variety of tissues, such as the vitreous of the eyes, umbilical cord, skeletal tissues, synovial fluid, heart valves, and skin [3] and initially thought to be principally structural. However, further investigation suggests that HA
Received July 15, 2019; accepted May 29, 2020 Correspondence: Maorong Wan
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