Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bisphosphonates are potent inhibitors of bone resorption in vivo and are emerging as important and widely used drugs for the treatment of a variety of abnormal bone resorptive processes. In the current study we investigated the in vitro effects of 4-amino-1-hydroxybutylidene-1,1-bisphosphonate (alendronate), a recently developed, extremely potent bisphosphonate, on the immune functions of human peripheral blood mononuclear cells (PBMCs). PBMC proliferation induced by lectins, alloantigens, and a nominal antigen (tetanus toxoid) was inhibited in a dose-dependent manner by alendronate. Pretreatment of monocytes, but not T cells, with the compound at concentrations ranging from 10(-4) to 10(-8) M was inhibitory, indicating that alendronate acts selectively on antigen-presenting cells (APCs). Alendronate did not affect the viability of monocytes or T cells or the expression of cell surface molecules known to play critical roles in antigen presentation. Alendronate exhibited dose-dependent inhibition of the production of interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) by activated monocytes. The inhibitory effect of 10(-6) M alendronate on PBMC proliferation was reversed by 10 U/ml recombinant rIL-1 beta, whereas other cytokines such as IL-6, TNF-alpha, and granulocyte-macrophage colony-stimulating factor (GM-CSF) had no effect. Thus, alendronate acts on monocytes to inhibit their antigen-presenting/accessory cell functions through a mechanism that can be overcome by exogenous IL-1. The inhibitory effect of this agent on cytokine production may contribute to its inhibitory effect on bone resorption.
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PMID:Inhibition of antigen-presenting cell function by alendronate in vitro. 859 49

Aminobisphosphonates inhibit bone resorption but have been shown to elicit acute-phase-like elevations in interleukin-6 (IL-6) in bone in vitro. The current studies were carried out to determine the relationship between the antiresorptive effects of the aminobisphosphonate alendronate and its effects on IL-6. Resorption was elicited in cultured 19-day fetal rat limb bones by 72 h treatment with interleukin-1beta (IL-1beta). Bone mass was quantitated at the end of the culture period to assess resorption. IL-6 was determined by bioassay (7TD1 cell proliferation). IL-1beta (18 and 180 pM) stimulated bone resorption and increased IL-6. Alendronate (70 microM) inhibited the IL-1beta-stimulated resorption. Alendronate alone did not affect IL-6 production by the bones. The IL-6 production from bones stimulated with 18 pM IL-1beta was not significantly affected by alendronate, but the IL-6 production from bones stimulated with 180 pM IL-1beta plus alendronate (21 and 70 microM) was higher than with IL-1beta alone. Indomethacin (1 mM) inhibited the IL-6 increase elicited by 180 pM IL-1beta and the enhanced IL-6 production elicited by cotreatment with IL-1beta and alendronate. Since bone cultures contain multiple cell types, further experiments were carried out to determine whether alendronate could increase IL-1beta-stimulated IL-6 production in an osteoblast cell line, UMR-106. Alendronate alone did not affect IL-6 in UMR-106 cells. Alendronate (70 microM) in combination with IL-1beta (180, 1.8, or 8 nM), or 7 microM alendronate, in combination with 8 nM IL-1beta, significantly increased IL-6 in 48 h cell cultures. The results from the bone organ cultures show that alendronate can enhance IL-6 production elicited by higher concentrations of the cytokine IL-1beta in bone, but that this effect on IL-6 does not prevent the inhibitory actions of alendronate on bone resorption. The results with the UMR106 cells indicate that one cellular site at which this enhancement of IL-6 production can occur is the osteoblast.
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PMID:Alendronate/interleukin-1beta cotreatment increases interleukin-6 in bone and UMR-106 cells: dose dependence and relationship to the antiresorptive effect of alendronate. 961 Jul 42

The objective of this study was to investigate the ability of alendronate and taurine in inhibiting in vitro osteoclast differentiation induced by bacteria. Whole cell sonicates of Porphyromonas gingivalis were used as an osteoclast-stimulating factor in a mouse coculture system and differentiated osteoclasts were confirmed by tartrate-resistant acid phosphatase (TRAP) staining. Alendronate at the concentrations of 10(-7) M, 10(-6) M, and 10(-5) M and taurine at the concentrations of 4 mM, 8 mM, and 12 mM were used. The cytotoxic effects of alendronate and taurine were examined using methylthiazole-tetrazolium bromide (MTT) assay. The amounts of interleukin-6 (IL-6) in culture supernatants were also measured using ELISA. The sonicates of P. gingivalis at the concentration of 0.01-0.1 microg/ml significantly stimulated the formation of osteoclasts (p < 0.05). Alendronate (10(-5) M) and taurine (12 mM) significantly suppressed the sonicate-stimulated osteoclast formation. In MTT assay, no cytotoxic effects were evident in all concentrations of alendronate and taurine. Alendronate and taurine did not affect the amount of IL-6 induced by P. gingivalis sonicates. These data indicate that alendronate and taurine have inhibitory effects on bacteria-stimulated osteoclast formation in vitro and that this inhibitory mechanism is not related to the blocking of IL-6 production.
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PMID:The inhibitory effect of alendronate and taurine on osteoclast differentiation mediated by Porphyromonas gingivalis sonicates in vitro. 1254 Feb 15

An autoimmune disease of rheumatoid arthritis (RA) causes severe inflammation on the synovial membrane, which results in the destruction of articular cartilage and bone. Here, Tocilizumab (TCZ)-Alendronate (ALD) conjugate is synthesized for the early intervention of RA. A humanized monoclonal antibody of TCZ shows an immunosuppressive effect, targeting interleukin-6 (IL-6) receptor in the RA pathogenesis. ALD is an anti-inflammatory bisphosphonate drug which can bind to the exposed bone surface. ALD is conjugated selectively to N-glycan on Fc region of TCZ using a chemical linker of 3-(2-pyridyldithio)propionyl hydrazide (PDPH)-poly(ethylene glycol)-N-hydroxysuccinimide (PDPH-PEG-NHS). The successful synthesis of TCZ-ALD conjugate is corroborated by 1H NMR, the purpald assay, mass spectrometry (MS), and high performance liquid chromatography (HPLC). In vitro binding affinity and cell viability tests confirmed the biological activity of TCZ-ALD conjugate. Furthermore, in vivo efficacy of TCZ-ALD conjugate is confirmed by microcomputed tomography (CT), histology, and Western blot analyses for the treatment of RA.
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PMID:Tocilizumab-Alendronate Conjugate for Treatment of Rheumatoid Arthritis. 2810 24