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)

Hematopoiesis is regulated by cytokines released from bone marrow stromal cells and mature leukocytes. Recent studies have identified these cells as targets for benzene-induced hematotoxicity. In the present studies we analyzed the effects of benzene treatment of mice on the production of interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) by bone marrow leukocytes. Bone marrow cells isolated from control or benzene-treated mice (660 mg/kg, once/day, 3 days) were purified on lymphocyte separation medium. Cells were then cultured in the presence of varying concentrations of lipopolysaccharide (0.1-10 micrograms/ml) for 0.5-48 hr. IL-1, IL-6, and TNF-alpha activity in culture supernatants was then quantified. We found a significant (p less than or equal to 0.02) increase in TNF-alpha production by bone marrow leukocytes from benzene-treated mice when compared to cells from control animals. Furthermore, this increase was dependent on the macrophage-specific growth factor, colony stimulating factor-1. Benzene treatment was also found to induce a small but significant (p less than or equal to 0.02) increase in the production of IL-1 by bone marrow leukocytes. This increase was rapid and transient, occurring in supernatants collected 2 hr after inoculation of bone marrow cells into culture. In contrast, benzene treatment had no effect on the production of IL-6 by bone marrow leukocytes. These results demonstrate that benzene treatment of mice stimulates mature bone marrow leukocytes to produce elevated levels of growth regulatory cytokines.
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PMID:Increased production of tumor necrosis factor-alpha by bone marrow leukocytes following benzene treatment of mice. 156 35

It is well known that several inflammatory cytokines can modulate hepatocellular gene expression in a complex physiological process known as the hepatic acute-phase response. Since hepatitis B virus (HBV) characteristically induces a vigorous lymphomononuclear inflammatory response in the liver during acute and chronic hepatitis, it is possible that hepatocellular HBV gene expression may also be modulated by one or more of the cytokines produced by these cells. Using bacterial lipopolysaccharide (LPS) as a surrogate inducer of inflammatory cytokines in vivo, we have tested this hypothesis in a transgenic mouse model system. In experiments with two independent transgenic mouse lineages that express the HBV envelope region under the control of either HBV or cellular promoters, we observed a 50 to 80% reduction in the hepatic steady-state content of a 2.1-kb HBV mRNA following administration of a single intraperitoneal dose of LPS. The regulatory influence of several inflammatory cytokines known to be induced by LPS was also examined in this system. The negative regulatory effect of LPS was consistently reproduced by the administration of a single nontoxic dose of tumor necrosis factor alpha, and it was occasionally observed following the administration of high doses of alpha interferon and interleukin-6, while no effect was detectable in response to high-dose interleukin-1 alpha or to gamma interferon. These observations suggest that tumor necrosis factor alpha and perhaps other cytokines may activate a heretofore unsuspected intracellular pathway that negatively regulates HBV gene expression. The intracellular mechanism(s) responsible for this effect and its pathophysiologic relevance remain to be elucidated.
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PMID:Tumor necrosis factor alpha negatively regulates hepatitis B virus gene expression in transgenic mice. 158 37

The rat hemopexin (Hx) gene was isolated and studies of its transcriptional regulation initiated. For analysis by a transient expression assay, the sequence between -2400 and +21 and sequential 5' truncates were linked to the chloramphenicol acetyltransferase (CAT) gene. HepG2 cells transfected with these CAT constructs were treated with conditioned medium of lipopolysaccharide stimulated human monocytes, interleukin-1 (IL-1) or interleukin-6 (IL-6). The activities of putative regulatory regions joined to the SV40 promoter indicated that the flanking region of the rat Hx gene from -209 to -104 contains three functional regions designated proximal regulatory regions; PRR-I (-209 to -173), -II (-178 to -158) and -III (-154 to -104). We found that PRR-II contains a different class of IL-6 responsive element (RE) from that reported for the human Hx gene, and that PRR-I and PRR-III participate in the basal expression of rat Hx in HepG2 cells.
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PMID:Identification of an interleukin-6 responsive element and characterization of the proximal promoter region of the rat hemopexin gene. 159 80

The time course of thromboxane B2 (TxB2), 6-keto-PGF1 alpha (stable metabolite of prostacyclin), tumor necrosis factor-alpha (TNF alpha), platelet activating factor (PAF), and interleukin-6 (IL-6) formation after three lipopolysaccharide (LPS) infusions was studied in pigs over an 18-hr, period. The Escherichia coli endotoxin W0111:B4 was injected i.v. into 10 of the test group pigs at a dose of 0.5 micrograms/kg over 30 min at 0, 5 and 10 hr of the experiment. Three pigs injected with physiological saline served as controls. At defined time points before and after each LPS administration venous blood was withdrawn (0, 15, 30, 45, 60, 120, 180 min) and plasma levels of TxB2, 6-keto-PGF 1 alpha, PAF, TNF alpha and IL-6 were determined. Pulmonary artery pressure (PAP) and cardiac output (CO) were measured every 15 min. TxB2 and PAF peaked significantly between 30 and 45 min, TNF alpha and 6-keto-PGF 1 alpha between 30 and 60 min, and IL-6 between 120 and 180 min after each LPS injection. The mediators PAF, TNF alpha and TxB2 showed a decreasing three-peak profile whereas 6-keto-PGF1 alpha exhibited an increasing one. IL-6 plasma concentrations increased after each LPS injection. The peak after the third LPS administration, however, was surprisingly low compared to the previous two. The first LPS infusion in our test group led to a significant, sustained rise in mean PAP. After recurrent LPS injections the peak in PAP was not as marked as after the first infusion, indicating the development of a tolerance towards LPS. Initially, CO showed hypodynamic values, whereas the end stage of the experiment was characterized by hyperdynamic CO levels. In conclusion, we believe this porcine model of septic shock to be one of the first large animal models to describe in detail the time-course of various important inflammatory mediators.
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PMID:Time course of various inflammatory mediators during recurrent endotoxemia. 159 96

Intraperitoneal (i.p.) injection of a mineral oil such as pristane induces a chronic inflammatory response in mice. This is characterized by a large influx of macrophages and other inflammatory cells into the peritoneal cavity for months after injection of the oil. By using the B9 cell bioassay, it was found that injection of pristane caused a marked and prolonged elevation of interleukin-6 (IL-6) levels in the peritoneal cavities of the mice. IL-6 was undetectable (less than 15 U/mL) in the peritoneal fluids of unprimed mice and during the first week after injecting pristane. From 4 to 20 weeks, the concentration of IL-6 increased to an apparent plateau with concentrations ranging from 200 to 2,000 U/mL. Increasing the dose of pristane did not substantially increase the peritoneal levels of IL-6 established at 20 weeks after pristane treatment. At later times (by day 250), the level decreased to 263 +/- 217 U/mL. However, mice that developed plasma cell tumors around day 300 showed high levels of IL-6 in the ascites fluid (650 to 2,400 U/mL). Serum levels of IL-6 were also elevated in pristane-primed mice but were substantially lower than those found in the peritoneal cavity. Chronic administration of the nonsteroidal anti-inflammatory drug indomethacin decreased the levels of IL-6 by 75% to 80%. Experiments performed in vitro showed that pristane-elicited macrophages secreted low levels of IL-6 constitutively and high levels of IL-6 in the presence of lipopolysaccharide. Both IL-6 and prostaglandin E2 production were inhibited by addition of indomethacin to macrophage cultures in vitro. Treatment of mice with pristane may provide a model system for studying the inflammatory pathways that control IL-6 levels in vivo. The relevance of these results to elucidation of the role of IL-6 in plasma cell tumorigenesis is discussed.
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PMID:Elevation of interleukin-6 in response to a chronic inflammatory stimulus in mice: inhibition by indomethacin. 161 Oct 85

While a number of clinical studies indicate that elevated serum cytokine [interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF)] levels are associated with enhanced mortality in sepsis, the time course and the role that different macrophage (M phi) populations play in releasing these cytokines remain to be determined. To study this, polymicrobial sepsis was induced in C3H/HeN mice by cecal ligation and puncture (CLP). The animals were then sacrificed at 1, 4, or 24 hr post-CLP. Blood was taken for serum cytokine level determination. Macrophages, of either peritoneal (PM phi) or alveolar (AM phi) origin, were harvested by lavage, and their innate vs. inducible cytokine productive capacities were assessed by incubation with or without endotoxin (lipopolysaccharide; LPS). Serum levels of TNF were significantly enhanced 1 hr post-CLP (CLP = 3.8 +/- 2.4* vs. sham = 0.4 +/- 0.9 U/ml; P less than 0.05 by t test). However, not until 4 hr post-CLP were marked increases in IL-6 observed (CLP = 318.0 +/- 209.0* vs. sham = 1.1 +/- 0.5 U/ml), which remained elevated through 24 hr post-CLP (CLP = 11.3 +/- 15.0* vs. sham = 0.03 +/- 0.02 U/ml). Cytokine release (IL-1, IL-6, TNF) from PM phi (without the addition of LPS) was detectable only in cells harvested 1 h following CLP. Alveolar M phi from septic mice showed little in vivo activation. Septic PM phi IL-1 and IL-6 production was markedly depressed at all time points with LPS stimulation, but TNF release remained unaltered.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Polymicrobial sepsis selectively activates peritoneal but not alveolar macrophages to release inflammatory mediators (interleukins-1 and -6 and tumor necrosis factor). 161 4

The endogenous adrenocortical response to sepsis is critical for host survival. The in vivo interactions among the endogenous glucocorticoid response, the induction of cytokines, and host survival during endotoxemia were explored in this study by use of the glucocorticoid receptor antagonist RU 486. Male Lewis rats underwent sterile insertion of a right jugular venous catheter. After a 72-h recovery period, animals received a 50% lethal dose of Escherichia coli endotoxin (2.5 mg/kg) via the catheter after pretreatment for 30 min prior to lipopolysaccharide (LPS) treatment with (i) vehicle alone intravenously (i.v.) (-corticosterone [-Cort]/-RU 486/+LPS) (n = 10), (ii) the antiglucocorticoid RU 486 (10 mg/kg) i.v. (-Cort/+RU 486/+LPS) (n = 11), or (iii) RU 486 (10 mg/kg) i.v. in animals that had undergone subcutaneous implantation of a corticosterone pellet at the time of catheter insertion (+Cort/+RU 486/+LPS) (n = 10). Except in animals receiving corticosterone pretreatment, baseline plasma corticosterone levels were low in all groups. Plasma corticosterone levels increased significantly (P less than 0.001) above the baseline following LPS administration. Animals in the -Cort/+RU 486/+LPS-treated group exhibited significantly increased mortality (P less than 0.001), with only 9% of the animals surviving at 72 h, as well as significantly increased plasma interleukin-6 levels, compared with animals receiving the vehicle alone (-Cort/-RU 486/+LPS), which showed 50% mortality. Pretreatment with corticosterone and RU 486 (+Cort/+RU 486/+LPS) significantly (P less than 0.001) reversed the mortality observed with RU 486 pretreatment alone (-Cort/+RU 486/+LPS), with 70% of the animals surviving at 72 h, and significantly attenuated the peak plasma tumor necrosis factor and interleukin-6 responses to LPS, compared with those in the animals treated with vehicle alone. These data demonstrate that the blockade of glucocorticoid binding by RU 486 increases LPS-induced mortality. The reversal of this effect by the induction of hypercorticosteronemia prior to RU 486 and LPS exposure (+Cort/+RU 486/+LPS) improves survival and is further associated with significant attenuation of cytokine production. Therefore, these data suggest that the protective effect of the endogenous glucocorticoid response to acute endotoxemia may result from the down-regulation of a potentially lethal cytokine response.
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PMID:In vivo effects of the antiglucocorticoid RU 486 on glucocorticoid and cytokine responses to Escherichia coli endotoxin. 161 34

Based on the immune-modulating properties of corticotropin-releasing factor (CRF), the effect of this peptide for interleukin-6 (IL-6) production was investigated. Using human peripheral blood mononuclear cells (MNC), the amount of bioactive IL-6 produced was significantly (P less than or equal to 0.05) increased by CRF (10(-10) to 10(-7) M range). However, the IL-6 production of lipopolysaccharide-treated MNC cultures was not modified. At concentrations of greater than or equal to 10 nM, CRF and two analogous peptides (Tyr-CRF and alpha-helical CRF) elicited 16- to 21-fold stimulation of IL-6 production by MNC. Purified monocytes, but not purified lymphocytes, were the cells that responded to CRF action exhibiting nearly 19-fold stimulation at 100 nM concentration. The CRF-induced production of IL-6 cytokine by peripheral blood MNC may suggest a messenger role for this neurohormone in the feedback control of neuroendocrine-immune circuitry.
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PMID:Stimulation of interleukin-6 production by corticotropin-releasing factor. 162 64

We have been investigating the production of cytokines in ocular tissues. In this paper, we demonstrated the in vitro production of interleukin-6 (IL-6) by human corneal epithelial, stromal and endothelial cells using enzyme-linked immunosorbent assay (ELISA). In culture supernatant of the stromal cells, the production of immunoreactive IL-6 was induced, depending upon the doses of lipopolysaccharide (LPS) or IL-1 alpha added into the culture. Detectable IL-6 activity in the supernatant of the stromal cells was found 2 hours after addition of IL-1 alpha and the activity increased to a peak level at 48 hours. On the other hand, in the supernatant of the endothelial cells, IL-6 activity was found even in unstimulated-culture, and induced further by LPS stimulation. The molecular weights (MWs) of the IL-6 produced by the epithelial, stromal and endothelial cells were calculated by gel filtration as about 30 kDa. From Western blotting analysis, the MW of IL-6 produced by the stromal cells was also determined to be 30 kDa.
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PMID:[Human corneal epithelial, stromal and endothelial cells produce interleukin-6]. 162 70

The strain-dependent expression of murine serum amyloid P-component (SAP) has been known to be linked to the Sap locus. We have quantified the SAP mRNA in several inbred strains including DBA/2 and C57BL/6 mice which represent high and low producers of SAP at resting state, respectively, and found that the mRNA levels correlated well with the amount of SAP protein. Interestingly, the SAP mRNA level of F1 mouse between DBA/2 and C57BL/6 was low and similar to that of C57BL/6. Primer extension and ribonuclease (RNAase) protection analyses demonstrated that a single type of transcript was generated from the SAP gene and that the cap sites were identical regardless mouse strains tested under unstimulated and stimulated (by lipopolysaccharide (LPS) or interleukin-6 (IL-6)) conditions. To investigate possible structural difference of the SAP gene including 5' flanking region, we have cloned, sequenced and compared the SAP genes from DBA/2 and C57BL/6 mice. Sequence analyses revealed that the 5' flanking regulatory regions, as well as the coding regions, were well-conserved between the two strains. These results demonstrate that the strain-dependent SAP expression occurs at the transcriptional level but seems to be affected by neither different type of the transcripts nor structural difference of the 5' flanking and coding regions of the SAP gene. It was suggested that a possible transcription factor with suppressive activity, which is encoded by a gene linked to Sap, may be involved.
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PMID:The strain-dependent constitutive expression of murine serum amyloid-P component is regulated at the transcriptional level. 162 42


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