title: Wear particles promote endotoxin tolerance in macrophages by inducing interleukin-1 receptor-associated kinase-M expression.
abstract: Toll-like receptors (TLRs) recognizing pathogen-associated molecular patterns (PAMP) play a role in local immunity and participate in implant-associated loosening. TLRs-mediated signaling is regulated by interleukin-1 receptor-associated kinase-M (IRAK-M). Our previous studies have proved that IRAK-M is induced by wear particles in macrophages from periprosthetic tissues. In this study, the IRAK-M-related mechanisms were further explored by lipopolysaccharide (LPS) and/or titanium (Ti) particles stimulations and small interfering RNAs (siRNAs). The protein level of IRAK-M was studied using western blotting and tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) levels were measured using ELISA. Results showed that in RAW264.7 cells stimulated by LPS after Ti particle pre-exposure, IRAK-M was slightly changed, compared with LPS stimulation. And levels of TNF-α and IL-1β in cultures stimulated by LPS first after Ti particle pre-exposure were lower than in the other two groups which were stimulated by LPS with or without Ti particles (p < 0.001), whereas there were no statistic differences between the later two (p > 0.05). The cytokines were lowest in Ti particles alone stimulation. After siRNAs silenced, IRAK-M-deficient cells exhibited increased expression of the cytokines in LPS stimulation after Ti particle pre-exposure and when stimulated with Ti particles alone. Our findings suggest that debris-induced IRAK-M decreases foreign body reactions, but at the same time, the over-expression of IRAK-M may also be detrimental on local intrusion of PAMPs or bacteria, negatively regulates the LPS-induced and TLRs-mediated inflammation and results in immunosuppression in periprosthetic tissue, which may predispose to implant-associated infections.
authors.affiliation: Huangpu Joint Centre, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510700, China.
authors.forename: Yangchun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Shiming
authors.initials: S
authors.lastname: Yu
authors.forename: Jianhong
authors.initials: J
authors.lastname: Xiao
authors.forename: Changhe
authors.initials: C
authors.lastname: Hou
authors.forename: Ziqing
authors.initials: Z
authors.lastname: Li
authors.forename: Ziji
authors.initials: Z
authors.lastname: Zhang
authors.forename: Qiyi
authors.initials: Q
authors.lastname: Zhai
authors.forename: Matti
authors.initials: M
authors.lastname: Lehto
authors.forename: Yrjö T
authors.initials: YT
authors.lastname: Konttinen
authors.forename: Puyi
authors.initials: P
authors.lastname: Sheng
mesh_terms: D000818:Animals; D002460:Cell Line; D005549:Foreign-Body Reaction / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation; D020868:Gene Silencing; D007108:Immune Tolerance / Q000187:drug effects*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D019736:Prostheses and Implants / Q000009:adverse effects*; D014025:Titanium / Q000009:adverse effects*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology
chemical_list: D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D014025:Titanium; D053592:Interleukin-1 Receptor-Associated Kinases; C507772:Irak3 protein, mouse