Hsu C.-C.Chuang W.-J.Chung C.-H.Chang C.-H.Peng H.-C.TUR-FU HUANG2021-05-312021-05-31201620452322https://scholars.lib.ntu.edu.tw/handle/123456789/564112Bacterial infection-induced sepsis is the leading cause of septic inflammatory disease. Rhodostomin (Rn), a snake venom disintegrin, was previously reported to interact with the αVβ3 integrin and the TLR4 on phagocyte in attenuating LPS-induced endotoxemia. In this report, we further evaluated the effects of Rn on TLR2-activated monocytes and its in vivo efficacy. Rn effectively suppressed the adhesion, migration, and cytokine release of Pam3CSK4-activated THP-1 cells. Rn specifically bound to integrin αVβ3 of TLR2-activated THP-1. Integrin αV and Akt siRNA transfection both restrained Pam3CSK4-elicited cytokine release. Rn decreased the Pam3CSK4-induced phosporylation of MAPKs, degradation of I?° B and activation of FAK, Akt, c-Src and Syk. The Pam3CSK4-induced translocation of MyD88, a central adaptor of TLR2, to the cell membrane was also inhibited by Rn treatment. In the polymicrobial inflammatory caecal ligation and puncture model, Rn significantly reduced pro-inflammatory cytokine and chemokine release, alleviated tissue injury and elevated survival rate in vivo. Taken together, in addition to inhibiting the activation of TLR4, Rn exhibits anti-inflammatory activity through antagonizing the activation of phagocytes and interrupting the crosstalk between αVβ3 and TLR2-dependent signaling pathways.[SDGs]SDG3chemokine; cytokine; peptide; rhodostomin; Tlr2 protein, mouse; toll like receptor 2; vitronectin receptor; animal; cell adhesion; cell line; cell motion; cytology; disease model; drug effects; gene expression regulation; human; male; metabolism; monocyte; mouse; sepsis; signal transduction; Animals; Cell Adhesion; Cell Line; Cell Movement; Chemokines; Cytokines; Disease Models, Animal; Gene Expression Regulation; Humans; Integrin alphaVbeta3; Male; Mice; Monocytes; Peptides; Sepsis; Signal Transduction; Toll-Like Receptor 2journal article10.1038/srep23387269874072-s2.0-84962516631