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TLR signaling that induces weak inflammatory response and SHIP1 enhances osteogenic functions.

ABSTRACT: Toll-like receptor (TLR)-mediated inflammatory response could negatively affect bone metabolism. In this study, we determined how osteogenesis is regulated during inflammatory responses that are downstream of TLR signaling. Human primary osteoblasts were cultured in collagen gels. Pam3CSK4 (P3C) and Escherichia coli lipopolysaccharide (EcLPS) were used as TLR2 and TLR4 ligand respectively. Porphyromonas gingivalis LPS having TLR2 activity with either TLR4 agonism (Pg1690) or TLR4 antagonism (Pg1449) and mutant E. coli LPS (LPxE/LPxF/WSK) were used. IL-1β, SH2-containing inositol phosphatase-1 (SHIP1) that has regulatory roles in osteogenesis, alkaline phosphatase and mineralization were analyzed. 3α-Aminocholestane (3AC) was used to inhibit SHIP1. Our results suggest that osteoblasts stimulated by P3C, poorly induced IL-1β but strongly upregulated SHIP1 and enhanced osteogenic mediators. On the contrary, EcLPS significantly induced IL-1β and osteogenic mediators were not induced. While Pg1690 downmodulated osteogenic mediators, Pg1449 enhanced osteogenic responses, suggesting that TLR4 signaling annuls osteogenesis even with TLR2 activity. Interestingly, mutant E. coli LPS that induces weak inflammation upregulated osteogenesis, but SHIP1 was not induced. Moreover, inhibiting SHIP1 significantly upregulated TLR2-mediated inflammatory response and downmodulated osteogenesis. In conclusion, these results suggest that induction of weak inflammatory response through TLR2 (with SHIP1 activity) and mutant TLR4 ligands could enhance osteogenesis.

SUBMITTER: Muthukuru M

PROVIDER: S-EPMC4472124 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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Project description:Inflammatory response plays a bidirectional regulatory role in myocardial infarction (MI). TLR signaling pathway plays an important role in the development of inflammation. Additionally, we discovered that CCRR is an anti-arrhythmic lncRNA in a prior work. Here we show, it is decreased in mice with 3-day MI followed by a sharp increase of pro-inflammatory cytokines and activation of the TLR pathway. Overexpression of CCRR could effectively inhibit the inflammatory response, reduce the infarct area, and improve cardiac function. And also reduced hypoxia-induced inflammation in cardiomyocytes and macrophages induced by IFN and LPS. It produced a similar protective effect in cardiomyocytes co-cultured with macrophages. Through microarray analysis, RNA-binding protein immunoprecipitation analysis, and other related experiments verification, TLR2 and TLR4 may be as potential targets of CCRR after MI. Our findings provide the evidence that lncRNA CCRR plays a key cardioprotective role against MI injury by targeting the TLR signaling pathway. nflammatory response plays a bidirectional regulatory role in myocardial infarction (MI). TLR signaling pathway plays an important role in the development of inflammation. Additionally, we discovered that CCRR is an anti-arrhythmic lncRNA in a prior work. Here we show, it is decreased in mice with 3-day MI followed by a sharp increase of pro-inflammatory cytokines and activation of the TLR pathway. Overexpression of CCRR could effectively inhibit the inflammatory response, reduce the infarct area, and improve cardiac function. And also reduced hypoxia-induced inflammation in cardiomyocytes and macrophages induced by IFN and LPS. It produced a similar protective effect in cardiomyocytes co-cultured with macrophages. Through microarray analysis, RNA-binding protein immunoprecipitation analysis, and other related experiments verification, TLR2 and TLR4 may be as potential targets of CCRR after MI. Our findings provide the evidence that lncRNA CCRR plays a key cardioprotective role against MI injury by targeting the TLR signaling pathway.

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TLR signaling that induces weak inflammatory response and SHIP1 enhances osteogenic functions.

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