Signal Transduction System for Interleukin-6 Synthesis Stimulated by Lipopolysaccharide in Human Osteoblasts

Kondo, Ayami; Koshihara, Yasuko; Togari, Akifumi

doi:10.1089/107999001753289550

Cited by 27 publications

(31 citation statements)

References 29 publications

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“…Similar findings have been observed with other agonists of IL-6 in osteoblasts and other cell types (4,17,26). The calculated IC 50 is 2.5μM of SB203580.…”

Section: Discussionsupporting

confidence: 87%

“…Previous studies have shown that PTH stimulates IL-6 production in osteoblasts through signaling intermediates including protein kinase (PK) A and PKC (24, 50), but not p38 MAPK. IL-1β, TNFα, and LPS all have been shown to increase p38 signaling in response to stimulation in osteoblasts (4,25,26,28). Addition data shows that IL-6 and eGFP mRNA expression are regulated in MC6 cells through p38 ( Figure 6C and 6D).…”

Section: Discussionmentioning

confidence: 84%

“…Importantly, it was shown that neutralization of IL-6 with antibodies or knockout of the IL-6 gene in mice prevents the upregulation of granulocyte macrophage-colony stimulating factor (GM-CSF) in the marrow, and the expected increase of osteoclast numbers in trabecular bone sections; and also protects the loss of bone following loss of sex steroids (1,21). This cytokine is produced by osteoblasts and is inducible by the pro-inflammatory cytokines IL-1, TNF, or bacterial-derived lipopolysacchride (LPS) as well as other osteotrophic hormones including parathyroid hormone (PTH) (6,12,19,26). IL-6 as well as IL-β, TNF-α, and macrophage-colony-stimulating factor (M-CSF) appear to be the major target genes for osteoclastogenesis (53).…”

Section: Introductionmentioning

confidence: 99%

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p38 MAPK Regulates IL‐1β Induced IL‐6 Expression Through mRNA Stability in Osteoblasts

Patil

Zhu

Rossa

et al. 2004

Immunological Investigations

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Osteoblast-derived IL-6 functions in coupled bone turnover by supporting osteoclastogenesis favoring bone resorption instead of bone deposition. Gene regulation of IL-6 is complex occurring both at transcription and post-transcription levels. The focus of this paper is at the level of mRNA stability, which is important in IL-6 gene regulation. Using the MC3T3-E1 as an osteoblastic model, IL-6 secretion was dose dependently decreased by SB203580, a p38 MAPK inhibitor. Steady state IL-6 mRNA was decreased with SB203580 (2μM) ca. 85% when stimulated by IL-1β (1 5ng/ml). These effects require de novo protein synthesis as they were inhibited by cycloheximide. p38 MAPK had minor effects on proximal IL-6 promoter activity in reporter gene assays. A more significant effect on IL-6 mRNA stability was observed in the presence of SB203580. Western blot analysis confirmed that SB203580 inhibited p38 MAP kinase, in response to IL-1β in a dose dependent manner in MC3T3-E1 cells. Stably transfected MC3T3-E1 reporter cell lines (MC6) containing green fluorescent protein (GFP) with the 3′ untranslated region of IL-6 was constructed. Results indicated that IL-1β, TNFα, LPS but not parathyroid hormone (PTH) could increase GFP expression of these reporter cell lines. Endogenous IL-6 and reporter gene eGFP-IL-6 3′ UTR mRNA was regulated by p38 in MC6 cells. In addition, transient transfection of IL-6 3′ UTR reporter cells with immediate upstream MAP kinase kinase-3 and -6 increased GFP expression compared to mock transfected controls. These results indicate that p38 MAPK regulates IL-1β-stimulated IL-6 at a post transcriptional mechanism and one of the primary targets of IL-6 gene regulation is the 3′ UTR of IL-6.

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“…Similar findings have been observed with other agonists of IL-6 in osteoblasts and other cell types (4,17,26). The calculated IC 50 is 2.5μM of SB203580.…”

Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

p38 MAPK Regulates IL‐1β Induced IL‐6 Expression Through mRNA Stability in Osteoblasts

Patil

Zhu

Rossa

et al. 2004

Immunological Investigations

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“…In osteoblasts, the signal transduction systems involved in stimulating IL-6 synthesis by LPS remain unclear. Using human osteoblastic cells, the transcriptional activation of AP-1 but not NF-B has been shown to mediate IL-6 synthesis in response to LPS (12). On the other hand, a recent study suggests that 15-deoxy-␦ (12, 14)-prostaglandin J(2) suppresses LPS-induced IL-6 expression in MC3T3E-1 cells via the Akt and NF-B pathways (37).…”

Section: Discussionmentioning

confidence: 99%

“…Inappropriate expression of IL-6 has been suggested to have an impact on the increase in bone resorption observed in several bone inflammatory diseases (10,11). Stimulation of IL-6 mRNA synthesis by LPS in human osteoblasts has been suggested to occur through CD14, p38 MAPK, and MEK (12). Several transcription factors such as NF-B and CCAAT/ enhancer-binding protein (C/EBP)␤ seem to be involved in IL-6 gene regulation in osteoblasts (13,14).…”

mentioning

confidence: 99%

Suppressor of Cytokine Signaling 3 Inhibits LPS-induced IL-6 Expression in Osteoblasts by Suppressing CCAAT/Enhancer-binding Protein β Activity

Yan

Cao

et al. 2010

Journal of Biological Chemistry

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Suppressor of cytokine signaling 3 (SOCS3) is an important intracellular protein that inhibits cytokine signaling in numerous cell types and has been implicated in several inflammatory diseases. However, the expression and function of SOCS3 in osteoblasts are not known. In this study, we demonstrated that SOCS3 expression was transiently induced by LPS in osteoblasts, and apparently contributed to the inhibition of IL-6 induction by LPS treatment. We found that tyrosine 204 of the SOCS box, the SH2 domain, and the N-terminal kinase inhibitory region (KIR) of SOCS3 were all involved in its IL-6 inhibition. Furthermore, we demonstrated that CCAAT/enhancerbinding protein (C/EBP) ␤ was activated by LPS (increased DNA binding activity), and played a key role in LPS-induced IL-6 expression in osteoblasts. We further provided the evidence that SOCS3 functioned as a negative regulator for LPS response in osteoblasts by suppressing C/EBP␤ DNA binding activity. In addition, tyrosine 204 of the SOCS box, the SH2 domain, and the N-terminal kinase inhibitory region (KIR) of SOCS3 were all required for its C/EBP␤ inhibition. These findings suggest that SOCS3 by interfering with C/EBP␤ activation may have an important regulatory role during bone-associated inflammatory responses. SOCS3 belongs to the family of suppressors of cytokine signaling (SOCS)2 proteins, which is induced by a number of mediators, including LPS, TNF-␣, as well as IL-6 and IL-10 (1-3). SOCS3 has been shown to function as a proinflammatory mediator by suppressing IL-6-gp130 signaling, interfering with its ability to inhibit LPS signaling (4, 5). For example, mice lacking SOCS3 in macrophages and neutrophils are resistant to LPS-induced shock (4). In contrast, accumulating data suggest that SOCS3 may suppress inflammatory responses (6). Thus, the function of SOCS3 during inflammation seems to be dependent on the particular disease model used and cell type studied. Moreover, the precise role of SOCS3 in LPS responses remains enigmatic.The stimulation of Toll-like receptor (TLR) 4 by LPS plays a critical role in innate immune responses in mammals. Although most studies on LPS-induced inflammation and the ensuing tissue destruction have been focused on immune systems, recent studies demonstrate that osteoblasts also express functional TLR4, which may play an important role in the pathogenesis of LPS-mediated bone disorders (2,7,8). For example, LPS stimulates osteoblasts to secrete receptor activator of NF-B ligand (RANKL), IL-6, IL-1, TNF-␣, GM-CSF, and PGE 2 , each of which seems to to be involved in LPS-mediated bone resorption (9). Among these proinflammatory mediators, IL-6 regulation in bone is extremely important for tissue homeostasis. Inappropriate expression of IL-6 has been suggested to have an impact on the increase in bone resorption observed in several bone inflammatory diseases (10, 11). Stimulation of IL-6 mRNA synthesis by LPS in human osteoblasts has been suggested to occur through CD14, p38 MAPK, and MEK (12). Several transcription factors s...

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The local inflammatory environment and microorganisms in “aseptic” loosening of hip prostheses

2007

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Long term loosening of hip prostheses remains an important problem in orthopedics. Although various loosening mechanisms have been proposed, the exact process is still unclear. Particle disease and the pressure theory are widely known and generally accepted hypotheses to explain long term implant failure. Each proposed mechanism recognizes a local inflammatory response in which macrophages represent the main cell-type and several proinflammatory and antiinflammatory cytokines (IL-1beta, IL-6, TNFalpha, IL-10, TGFbeta), chemokines (IL-8/CXCL8, MCP-1/CCL2, RANTES/CCL5, MIP-1alpha/CCL3) and other mediators (GM-CSF, M-CSF, MMP-1, PDGF-alpha, PGE(2), IL-11) are identified. The cytokines have different functions and some are capable of stimulating bone resorption in various ways; either directly or indirectly. Even though the implant loosening is thought to be "aseptic", several studies suggested a possible role for bacteria and a bacterial biofilm in implant failure. Biofilm-derived bacteria and bacterial products might have an underestimated and potential role in the loosening process. In this article we will discuss the possible role of a bacterial biofilm and the importance of the local surrounding environment in "aseptic" loosening of hip prostheses.

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Signal Transduction System for Interleukin-6 Synthesis Stimulated by Lipopolysaccharide in Human Osteoblasts

Cited by 27 publications

References 29 publications

p38 MAPK Regulates IL‐1β Induced IL‐6 Expression Through mRNA Stability in Osteoblasts

p38 MAPK Regulates IL‐1β Induced IL‐6 Expression Through mRNA Stability in Osteoblasts

Suppressor of Cytokine Signaling 3 Inhibits LPS-induced IL-6 Expression in Osteoblasts by Suppressing CCAAT/Enhancer-binding Protein β Activity

The local inflammatory environment and microorganisms in “aseptic” loosening of hip prostheses

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