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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-l-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-κB (NF-κB),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 anti-inflammatory 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,IκBα,JNK1/2,ERK1/2,p38,and IRF-3.In conclusion,our results demonstrated that the B-HA attenuated the LPS-stimulated 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.