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)

Bone morphogenetic protein 2 (BMP2), a member of the transforming growth factor-beta (TGF-beta) superfamily, regulates a variety of cell fates and functions. At present, the molecular mechanism by which BMP2 induces apoptosis has not been fully elucidated. Here we propose a BMP2 signaling pathway that mediates apoptosis in mouse hybridoma MH60 cells whose growth is interleukin-6 (IL-6)-dependent. BMP2 dose-dependently induces apoptosis in MH60 cells even in the presence of IL-6. BMP2 has no inhibitory effect on the IL-6-induced tyrosine phosphorylation of STAT3, and the bcl-2 gene expression which is known to be regulated by STAT3, suggesting that BMP2-induced apoptosis is not attributed to alteration of the IL-6-mediated bcl-2 pathway. We demonstrate that BMP2 induces activation of TGF-beta-activated kinase (TAK1) and subsequent phosphorylation of p38 stress-activated protein kinase. In addition, forced expression of kinase-negative TAK1 in MH60 cells blocks BMP2-induced apoptosis. These results indicate that BMP2-induced apoptosis is mediated through the TAK1-p38 pathway in MH60 cells. We also show that MH60-derived transfectants expressing Smad6 are resistant to the apoptotic signal of BMP2. Interestingly, this ectopic expression of Smad6 blocks BMP2-induced TAK1 activation and p38 phosphorylation. Moreover, Smad6 can directly bind to TAK1. These findings suggest that Smad6 is likely to function as a negative regulator of the TAK1 pathway in the BMP2 signaling, in addition to the previously reported Smad pathway.
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PMID:BMP2-induced apoptosis is mediated by activation of the TAK1-p38 kinase pathway that is negatively regulated by Smad6. 1074

Etiological evidence, indicating the relationships between the onset of malignant lymphoma and pre-existing chronic inflammation, has been accumulated. For the autonomous growth of malignant tumor, genetic lesions, such as chromosomal aberrations, amplification of oncogenes, and mutations of genes involved in the cell cycle regulation, must be essential. However, how the inflammation promotes the accumulation of genetic lesions and induces the autonomous growth of lymphoid cells remains unclear. Reactive oxygen species released by polymorphonuclear leukocytes and macrophages are factors causing DNA damage in the foci of inflammation, and thus could play a role in lymphomagenesis. The xanthine/xanthine oxidase (X/XOD) system produces a mixture of hydrogen peroxide and superoxide anion extracellularly, and thus serves as an in vitro source of reactive oxygen species. Cell death of lymphoblastoid cell lines (LCLs) was induced with X/XOD treatment in a dose-dependent manner. DNA fragmentation, which is the characteristic feature of apoptosis, was observed in LCLs at 4-8 hours after X/XOD treatment. Among cytokines such as interleukin-6 (IL-6), IL-10, and interferon-gamma, only pretreatment with IL-6 gave LCLs the resistance to X/XOD-induced cell death in a dose-dependent manner. The proportion of apoptotic cells in X/XOD-treated LCL culture was decreased with IL-6 pretreatment by quantification with flow cytometric analysis. Treatment of LCLs with IL-6 for 48 hours up-regulated bcl-2 mRNA expression. Furthermore, the LCLs repeatedly treated with X/XOD and cultured with or without IL-6 showed many more structural abnormalities of chromosomes than those without X/XOD treatment. Colony forming efficiency of X/XOD-treated LCLs with IL-6 was significantly higher than those without IL-6, and even relatively higher than LCLs without X/XOD treatment. IL-6 could support the survival of non-neoplastic B cells and accelerate the malignant transformation of B lineage cells in inflammatory lesions.
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PMID:Induction of chromosomal aberrations and growth-transformation of lymphoblastoid cell lines by inhibition of reactive oxygen species-induced apoptosis with interleukin-6. 1083 Jul 83

Excessive hepatectomy often causes fatal hepatic failure, but the mechanism is unknown. We used a novel protocol of partial 90 and 95% hepatectomy (PHx) to investigate this mechanism in 2 groups of rats. The 90% PHx rats survived, but the 95% PHx animals died of hepatic failure. In the latter, cytokine (interleukin-6, tumor necrosis factor-alpha) levels and the apoptotic hepatocyte count increased, and there were few mitotic cells. By contrast, in the 90% PHx rats, the mitotic cell count increased, and more anti-apoptotic Bcl-xL protein was expressed. These results demonstrate that expression of Bcl-xL protein as an anti-apoptotic factor or regeneration factor contributes to survival after 90% PHx. Using an adenovirus vector, the human bcl-2 gene (hbcl-2) was therefore transfected to DA rat livers where it was efficiently expressed, and then 95% PHx was performed. Liver damage was decreased and the apoptotic cell count decreased too, but the rats died. We concluded that transfection of the hbcl-2 gene partly prevents cytotoxicity (apoptosis), but cannot ensure survival. Thus, some other factor is required (e.g., a regeneration stimulator) to maintain life in these models.
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PMID:Expression of Bcl-2 family reduces apoptotic hepatocytes after excessive hepatectomy. 1134 Feb 66

Weightlessness induces bone loss in humans and animal models. We employed the NASA-approved Rotating Wall Vessel bioreactor (RWV) to develop osteoblast-like cell cultures under microgravity and evaluate osteoblast phenotype and cell function. Rat osteoblast-like cell line (ROS.SMER#14) was grown in the RWV at a calculated gravity of 0.008g. For comparison, aliquots of cells were grown in conventional tissue culture dishes or in Non-Rotating Wall Vessels (N-RWV) maintained at unit gravity. In RWV, osteoblasts showed high levels of alkaline phosphatase expression and activity, and elevated expression of osteopontin, osteocalcin, and bone morphogenetic protein 4 (BMP-4). In contrast, the expression of osteonectin, bone sialoprotein II and BMP-2 were unaltered compared to cells in conventional culture conditions. These observations are consistent with a marked osteoblast phenotype. However, we observed that in RWV osteoblasts showed reduced proliferation. Furthermore, DNA nucleosome-size fragmentation was revealed both morphologically, by in situ staining with the Thymine-Adenine binding dye bis-benzimide, and electrophoretically, by DNA laddering. Surprisingly, no p53, nor bcl-2/bax, nor caspase 8 pathways were activated by microgravity, therefore the intracellular cascade leading to programmed cell death remains to be elucidated. Finally, consistent with an osteoclast-stimulating effect by microgravity, osteoblasts cultured in RWV showed upregulation of interleukin-6 (IL-6) mRNA, and IL-6 proved to be active at stimulating osteoclast formation and resorbing activity in vitro. We conclude that under microgravity, reduced osteoblast life span and enhanced IL-6 expression may result in inefficient osteoblast- and increased osteoclast-activity, respectively, thus potentially contributing to bone loss in individuals subjected to weightlessness.
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PMID:Characterization of the osteoblast-like cell phenotype under microgravity conditions in the NASA-approved Rotating Wall Vessel bioreactor (RWV). 1189 60

Aberrant expression of genes regulating apoptosis/survival seems to be essential in the stepwise development of human multiple myeloma (MM). In this paper we have compared the expression of bcl-2 family pro- and anti-apoptotic genes in MM cell lines, primary MM cells and normal plasma cells. The Bcl-2, Mcl-1, Bcl-xL/S, Bcl-w, Bax, Bak, and Bad were shown to be expressed in both malignant and non-neoplastic, normal plasma cells. Quantitative analysis revealed that the malignant phenotype seemed to correlate with an elevated expression of Mcl-1, a decreased expression of Bax and, to a lesser extent, an increased Bcl-2/Bax expression ratio. The possible influence of interleukin-6 (IL-6) in regulating the expression of the bcl-2-related genes was also examined. Using the IL-6-dependent MM cell lines U-1958 and U-266-1970 it was clearly shown that IL-6 deprivation induced cell cycle arrest in both cell lines, whereas apoptosis was only detected in the U-1958 cells. Furthermore, the anti-apoptotic proteins Bcl-2, Mcl-1 and Bcl-xL were down-regulated, while the expression of the pro-apoptotic Bax protein was increased. To conclude, we suggest that the expression pattern of the Bcl-2 family of proteins separates the malignant phenotype of MM from normal plasma cells, and that the protecting effect of IL-6 may be conducted via an altered balance between these proteins.
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PMID:Expression of the bcl-2 family of pro- and anti-apoptotic genes in multiple myeloma and normal plasma cells: regulation during interleukin-6(IL-6)-induced growth and survival. 1236 10

The aberrant behavior of cancer reflects upregulation of certain oncogenic signaling pathways that promote proliferation, inhibit apoptosis, and enable the cancer to spread and evoke angiogenesis. Theoretically, it should be feasible to decrease the activity of these pathways-or increase the activity of pathways that oppose them-with noncytotoxic agents. Since multiple pathways are dysfunctional in most cancers, and cancers accumulate new oncogenic mutations as they progress, the greatest and most durable therapeutic benefit will likely be achieved with combination regimens that address several targets. Thus, a multifocal signal modulation therapy (MSMT) of cancer is proposed. This concept has already been documented by researchers who have shown that certain combinations of signal modulators-of limited utility when administered individually-can achieve dramatic suppression of tumor growth in rodent xenograft models. The present essay attempts to guide development of MSMTs for prostate cancer. Androgen ablation is a signal-modulating measure already in standard use in the management of delocalized prostate cancer. The additional molecular targets considered here include the type 1 insulin-like growth factor receptor, the epidermal growth factor receptor, mammalian target of rapamycin, NF-kappaB, hypoxia-inducible factor-1alpha, hsp90, cyclooxygenase-2, protein kinase A type I, vascular endothelial growth factor, 5-lipoxygenase, 12-lipoxygenase, angiotensin II receptor type 1, bradykinin receptor type 1, c-Src, interleukin-6, ras, MDM2, bcl-2/bclxL, vitamin D receptor, estrogen receptor-beta, and PPAR-. Various nutrients and phytochemicals suspected to have potential utility in prostate cancer prevention and therapy, but whose key molecular targets are still unknown, might reasonably be incorporated into MSMTs for prostate cancer; these include lycopene, selenium, green tea polyphenols, genistein, and silibinin. MSMTs can be developed systematically by testing various combinations of signal-modulating agents, in concentrations that can feasibly be achieved and maintained clinically, on human prostate cancer cell lines; combinations that appear promising can then be tested in xenograft models and, ultimately, in the clinic. Some signal modulators can increase response to cytotoxic drugs by upregulating effectors of apoptosis. When MSMTs fail to raise the spontaneous apoptosis rate sufficiently to achieve tumor stasis or regression, incorporation of appropriate cytotoxic agents into the regimen may improve the clinical outcome.
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PMID:Targeting multiple signaling pathways as a strategy for managing prostate cancer: multifocal signal modulation therapy. 1552 6

Primary cutaneous plasmacytoma is a rare type of cutaneous B-cell lymphoma, characterized by clonal proliferation of plasma cells, that primarily develops in the skin. Five cases have been described to date in which a local triggering stimulus may be involved in development of this skin tumour. We describe the case of a primary cutaneous plasmacytoma localized to the lower lip. This site had been affected for 15 years with recurrent herpes simplex virus-1 infection. Neoplastic plasma cells were found to be bcl-2-positive. We hypothesize that chronic stimulation of keratinocytes by herpes simplex virus-1, possibly through toll-like receptors, may have favoured the release of cytokines (e.g. interleukin-6) able to induce plasma cell proliferation, transformation and survival.
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PMID:Primary cutaneous plasmacytoma: a role for a triggering stimulus? 1580 75

Interleukin-6 (IL-6) has been shown to rescue enterocytes from hypoxia-induced apoptosis when given orally following hemorrhagic shock. In vitro models using an intestinal epithelial cell line (IEC-6) cultured with lipopolysaccharide (LPS) under low O2 conditions, to mimic intestinal conditions, show that these cells also undergo apoptosis, which can be reduced by subsequent culture with IL-6. To examine further the mechanisms of rescue, we cultured normal rat intestinal epithelial cells (IEC-6) under both normoxic and hypoxic conditions and analyzed their responses to LPS and IL-6. We showed that IEC-6 expressed IL-6 receptor on its surface. Further, IEC-6 cells could be rescued from hypoxia-induced apoptosis by co-culture with IL-6. RNase protection assay (RPA) examination revealed that under hypoxic conditions, IEC-6 cells that were resistant to apoptosis showed reduced fas expression and increased bcl-2 expression after co-culture with LPS+IL-6.
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PMID:IL-6 protects enterocytes from hypoxia-induced apoptosis by induction of bcl-2 mRNA and reduction of fas mRNA. 1687 Jan 48

We hypothesized that spleen microarray gene expression profiles analyzed with contemporary pathway analysis software would provide molecular pathways of interest and target genes that might help explain the effect of bcl-2 on improving survival during sepsis. Two mouse models of sepsis, cecal ligation and puncture and tracheal instillation of Pseudomonas aeruginosa, were tested in both wild-type mice and mice that overexpress bcl-2. Whole spleens were obtained 6 h after septic injury. DNA microarray transcriptional profiles were obtained using the Affymetrix 430A GeneChip, containing 22,690 elements. Ingenuity Pathway Analysis software was used to construct hypothetical transcriptional networks that changed in response to sepsis and expression of the bcl-2 transgene. A conservative approach was used wherein only changes induced by both abdominal and pulmonary sepsis were studied. At 6 h, sepsis induced alterations in the abundance of hundreds of spleen genes, including a number of proinflammatory mediators (e.g., interleukin-6). These sepsis-induced alterations were blocked by expression of the bcl-2 transgene. Network analysis implicated a number of bcl-2-related apoptosis genes, including bcl2L11 (bim), bcl-2L2 (bcl-w), bmf, and mcl-1. Sepsis in bcl-2 transgenic animals resulted in alteration of RNA abundance for only a single gene, ceacam1. These findings are consistent with sepsis-induced alterations in the balance of pro- and anti-apoptotic transcriptional networks. In addition, our data suggest that the ability of bcl-2 overexpression to improve survival in sepsis in this model is related in part to prevention of sepsis-induced alterations in spleen transcriptional responses.
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PMID:Surviving sepsis: bcl-2 overexpression modulates splenocyte transcriptional responses in vivo. 1723 57

The present study is part of a large-scale investigation of the antitumor effects of Biophytum sensitivum on B16F-10 melanoma cells. The investigation involved the regulatory effect of B sensitivum on nitric oxide and cytokine production in B16F-10 cells, tumor-associated macrophages, and peritoneal macrophages as well as on the apoptotic process in B16F-10 melanoma cells. B sensitivum at a concentration of 10 microg/mL could significantly (P< .001) inhibit production of nitric oxide and proinflammatory cytokines such as interleukin-1beta, interleukin-6, granulocyte monocyte-colony stimulating factor, and tumor necrosis factor-alpha in B16F-10 cells, tumor-associated macrophages, and peritoneal macrophages. Incubation of B16F-10 cells with B sensitivum showed the presence of apoptotic bodies and induced DNA fragmentation. Furthermore, B sensitivum showed an inhibitory effect on inducible nitric oxide synthase as well as bcl-2 expression, and up-regulated p53 and caspase-3 messenger RNA expression in B16F-10 melanoma cells. The observed results suggest that regulation of proinflammatory cytokine production by tumor cells, tumor-associated macrophages, and resident macrophages accompanied by altered inducible nitric oxide synthase, bcl-2, caspase-3, and p53 messenger RNA expression by B sensitivum methanol extract induces apoptosis in B16F-10 melanoma cells.
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PMID:Apoptotic effect of Biophytum sensitivum on B16F-10 cells and its regulatory effects on nitric oxide and cytokine production on tumor-associated macrophages. 1804 85


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