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)

Taurine (Tau) is an exceptionally abundant free amino acid in the cytosol of inflammatory cells and especially in neutrophils. Taurine protects cells from self-destruction during processes that generate oxidants. The major function of Tau in leukocytes is to trap chlorinated oxidants (HOCl). Taurine reacts with HOCl to produce the long-lived compound taurine chloramine (TauCl). Previously, we have shown that other products of the neutrophil chlorinating system are able to modify functions of macrophages. In this study, we investigated in vitro the influence of TauCl on the generation of inflammatory mediators by activated macrophages. We have found that TauCl inhibited the generation of nitric oxide, prostaglandin E2, tumor necrosis factor alpha, and interleukin-6, but TauCl slightly enhanced the release of IL-1 alpha. The formation of nitrites by interferon-gamma-activated macrophages was inhibited by TauCl in a dose-dependent manner. Taurine chloramine also reduced the level of inducible nitric oxide synthase (iNOS) mRNA in macrophages, in a similar concentration-dependent manner. Although our experiments do not exclude a direct effect of TauCl on enzymatic activity of iNOS, the inhibition of iNOS expression seems to be the major mechanism responsible for suppression of NO formation. Finally, we discuss the biological role of TauCl in vivo. We suggest that at the site of inflammation TauCl works as a specific signaling molecule of activated neutrophils that coordinates the generation of inflammatory mediators in macrophages.
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PMID:Taurine chloramine, a product of activated neutrophils, inhibits in vitro the generation of nitric oxide and other macrophage inflammatory mediators. 749 64

To clarify the mechanism involved in regulating the secretion of albumin and alpha 1-acid glycoprotein by rat hepatocytes, we studied hepatocyte culture and cocultures of hepatocyte and liver nonparenchymal cells. The secretion of alpha 1-acid glycoprotein by hepatocytes was stimulated and that of albumin was inhibited by combinations of dexamethasone and monokines, especially by dexamethasone and interleukin-6. The secretion of these proteins was equally inhibited during stimulation by lipopolysaccharide in cocultures. The inhibitory effect of sinusoidal endothelial cells was smaller than that of Kupffer cells. This inhibition was partially abolished by blocking the nitric oxide synthase pathway in cocultured cells and was completely abolished by dexamethasone. In conclusion, the secretion of albumin and alpha 1-acid glycoprotein by hepatocytes was regulated by monokines, dexamethasone, and the inducible nitric oxide synthase pathway in hepatocytes and liver nonparenchymal cells in vitro.
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PMID:Regulation of hepatocyte albumin and alpha 1-acid glycoprotein secretion by monokines, dexamethasone, and nitric oxide synthase pathway: significance of activated liver nonparenchymal cells. 751 18

Administration of whole-cell diphtheria and tetanus toxoids and pertussis vaccine adsorbed (DTP vaccine) caused marked depression in the expression of mRNA for isozymes of cytochrome P-450 in the livers of endotoxin-responsive and nonresponsive mice. The levels of expression of mRNA for a polycyclic aromatic hydrocarbon-inducible (CYP1A2) and an ethanol-inducible (CYP2E1) form of P-450 were reduced by 70% to 80% 8 to 12 hr after vaccination or Bordetella pertussis endotoxin administration. These effects are preceded by marked increases (threefold to sixfold) in mRNA expression for interleukin-6, interleukin-1 and tumor necrosis factor in both strains of mice, with maximal increases 1 to 2 hr after injection. This is the first demonstration that levels of cytokine mRNA are altered in the liver in response to DTP vaccine administration. The finding of increased cytokine mRNA in the livers of mice injected with vaccine supports a role for cytokines as mediators of the decreased levels of cytochrome P-450. In addition, inducible nitric oxide synthase mRNA expression is also increased after vaccine administration, with a peak at 4 hr. The temporal relationship of the increased cytokine mRNA expression, increased nitric oxide synthase and decreased expression of P-450 mRNAs suggests a mechanism by which cytokines mediate the induction of nitric oxide synthase, which increases nitric oxide and decreases the activities of some cytochromes P-450.
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PMID:Modulation of hepatic mRNA levels after administration of lipopolysaccharide and diphtheria and tetanus toxoids and pertussis vaccine adsorbed (DTP vaccine) to mice. 752 68

Inducible nitric oxide synthase, the critical enzyme responsible for the enhanced synthesis of nitric oxide in inflammatory states, is widely expressed in mammalian cells. To evaluate potential regulatory roles of the 5'-untranslated region (UTR) in the human inducible nitric oxide synthase gene, the transcription initiation sites and structure of the 5'-UTR of human inducible nitric oxide synthase were examined. Freshly isolated human alveolar macrophages, bronchial epithelial cells, and several types of cultured cells were evaluated following stimulation with cytokines (i.e. interferon-gamma, interleukin-1 beta, tumor necrosis factor-alpha, and interleukin-6). The mRNA was analyzed by reverse transcription-polymerase chain reaction. Northern analysis, and 5'-rapid amplification of cDNA ends. Despite the presence of a TATA box in the promoter region, multiple transcription initiation sites were observed, some extending several hundred base pairs upstream from the main TATA-directed initiation site. Alternative splicing in the 5'-UTR of human inducible nitric oxide synthase mRNA resulted in further diversity. The TATA-independent inducible nitric oxide synthase mRNA transcripts were up-regulated by cytokines. The long and complex 5'-UTRs contain eight partially overlapping open reading frames upstream of the putative inducible nitric oxide synthase ATG, which may have an important role in translational regulation of human inducible nitric oxide synthase mRNA.
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PMID:Structural diversity in the 5'-untranslated region of cytokine-stimulated human inducible nitric oxide synthase mRNA. 753 35

A key manifestation of chronic rejection is an obliterative arteriosclerosis. Myointimal thickening in the vessel is preceded by an endothelialitis involving accumulation of host mononuclear cells in the perivascular and intimal spaces. We report a paratopic LEW-to-F344 rat carotid artery transplantation model developed to study the cells, cytokines, and inflammatory response associated with this early phase of vascular immune injury. Compared with contralateral control arteries and isografts, LEW-to-F344 carotid allografts develop intimal thickening with mononuclear cell infiltration that persists (days 20, 45, 75, 90, and 120). Allografted vessels had dense collections of intimal and adventitial leukocytes (CD45+) consisting of equal numbers of T cells and macrophages. There were small but variable numbers of intimal smooth muscle cells. Intimal cells showed dense staining for tumor necrosis factor-alpha, interleukin-8, platelet-derived growth factor, iNOS, and ICAM and weaker labeling for interleukin-1 beta and interleukin-6. There was also prominent staining for interleukin-4 and interleukin-7 with no detectable interferon-gamma or interleukin-2 staining and high titer labeling for IgG1 (but not IgG2). The predominance of the T cell infiltrate coupled with interleukin-4 and IgG1 expression in carotid allografts is consistent with a TH2 response. This contrasts with balloon-injured rat carotids, which evoke a macrophage-dependent proliferative response. These findings demonstrate that there are distinct as well as common activation pathways in various forms of vascular injury and the LEW-to-F344 carotid model provides the opportunity to gain insight into molecular mechanisms regulating alloimmune injury in the vessel.
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PMID:LEW-to-F344 carotid artery allografts: analysis of a rat model of posttransplant vascular injury involving cell-mediated and humoral responses. 854 91

Induction of hepatic nitric oxide synthase (NOS) by tumor necrosis factor-alpha (TNF alpha), interleukin-1 beta (IL-1 beta), interferon-gamma (IFN gamma), interleukin-6 (IL-6), and lipopolysaccharide was assessed as activity and immunoreactive protein. Hepatic NOS activity was cytosolic and had cofactor requirements consistent with inducible nitric oxide synthase (NOS2). NOS induction by TNF alpha was dose dependent from concentrations of 0.06 to 60 nM and was increased 2-3-fold by IFN gamma. NOS induction was reflective of total TNF alpha binding to hepatocyte receptors. Hepatocyte TNF alpha binding fit a biphasic curve with high affinity (K(d) = 1.4 nM, Bmax = 3157 sites) and low affinity (K(d) = 157 nM, Bmax = 204,948 sites) elements. NOS2 activity was induced by lipopolysaccharide, IL-1 beta, TNF alpha, and IFN gamma but not by IL-6. All cytokine stimuli were inhibited by antioxidants. Oxygen radical generation was directly measured as dichlorofluoroscein fluorescence in isolated mitochondria. Mitochondria from TNF alpha-treated hepatocytes generated more oxygen radicals than did controls. Antioxidants reduced mitochondrial generation of oxygen radicals. Activation of the transcription factor nuclear factor-kappa B by TNF alpha, IFN gamma, and IL-1 beta was assessed by gel shift analysis. Cytokine treatment increased nuclear factor-kappa B binding, and the addition of antioxidants or rotenone inhibited cytokine activation. Taken together, these data suggest that oxygen radicals, possibly generated by mitochondria, play a major role in NOS2 induction by cytokines.
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PMID:Characterization of hepatic nitric oxide synthase: identification as the cytokine-inducible form primarily regulated by oxidants. 870 Jan 34

To investigate the influence of inducible nitric oxide synthase on cerebral arteries after subarachnoid haemorrhage (SAH) in vivo, lipopolysaccharide (LPS), a major inducer of inducible nitric oxide synthase, was injected intracisternally into control and SAH model dogs. Intracisternal injection of LPS (0.5 mg) produced a long-lasting, submaximal vasodilation of the basilar artery of control dogs on angiography. This effect became significant at 4 hours after LPS injection and plateaued after 6 hours. This vasodilation was reduced by N(G)-monomethyl-L-arginine. Vasopressin slightly suppressed the vasodilation, while bradykinin increased it. The concentration of L-arginine in CSF decreased after LPS injection, while that of L-citrulline increased. In cytokines, the concentration of tumour necrosis factor-alpha; (TNF-alpha;) in CSF increased transiently at 4 hours after LPS injection, while interleukin-1 beta, interleukin-6, interferon-gamma, did not change. These data suggest that vasodilation by LPS is mainly due to nitric oxide predominantly synthesized by an inducible nitric oxide synthase, proximally induced by TNF-alpha. Our data make it unlikely that SAH itself induces the inducible nitric oxide synthase in vascular tissue, since isolated endothelium-denuded basilar artery from SAH model dogs did not respond to L-arginine. In SAH model dogs, the degree of vasodilation by LPS differed with the severity of vasospasm. Vasodilation was much greater in mild than in severe vasospasm in dogs, and was increased by superoxide dismutase. These findings suggest that the induction of inducible nitric oxide synthase or its activity may be less effective in severe vasospasm.
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PMID:Vasodilation by intrathecal lipopolysaccharide of the cerebral arteries after subarachnoid haemorrhage in dogs. 886 3

The role of Rel in the monocyte/macrophage lineage was examined in mice with an inactivated c-rel gene. Although the frequency of monocytic cells was normal in Rel-/- mice, we show that Rel serves distinct roles in regulating gene expression and immune effector function in different mature macrophage populations. Stimulated Rel-/- resident peritoneal macrophages produced higher than normal levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6), but tumour necrosis factor-alpha (TNF-alpha) production was not induced. Diminished cytotoxic activity exhibited by resident Rel-/- macrophages was consistent with reduced nitric oxide production resulting from impaired up-regulation of inducible nitric oxide synthase expression. While a similar altered pattern of IL-6 and TNF-alpha expression was observed in stimulated Rel-/- peritoneal effusion macrophages, cytotoxic activity, nitric oxide, GM-CSF and G-CSF production by these cells was normal. The alternate regulation of certain genes in the two macrophage populations coincided with different patterns of nuclear Rel/NF-kappaB complexes expressed in normal resident and elicited cells. Collectively, these results establish that Rel is a positive or negative regulator of transcription in macrophages and that Rel has distinct roles in different macrophage populations.
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PMID:The Rel subunit of NF-kappaB-like transcription factors is a positive and negative regulator of macrophage gene expression: distinct roles for Rel in different macrophage populations. 900 85

We have previously proposed that pro-inflammatory cytokines and nitric oxide (NO) contributed to reversible myocardial depression in patients with sepsis and congestive heart failure. Sepsis and heart failure are also associated with refractoriness to beta-adrenoceptor agonists. Therefore, the chronotropic effects of cytokines and the NO synthase inhibitor, NG-methyl-L-arginine (NMA), on beta-adrenoceptor stimulation of neonatal cardiac myocytes were studied. Tumor necrosis factor alpha, interleukin-1 beta and interleukin-6 but not interleukin-4 or interleukin-5 significantly enhanced spontaneous beating rates compared to untreated myocytes in serum-free media for 48 h (P < 0.01; n = 12 for each). NMA also significantly enhanced spontaneous beating rates (P < 0.01; n = 12 for each). Only interleukin-1 beta treatment resulted in significant nitrite production, immunohistochemical staining for inducible nitric oxide synthase and detection of inducible NO synthase messenger RNA by reverse transcriptase-polymerase chain reaction (RT-PCR). However, tumor necrosis factor alpha, interleukin-1 beta, interleukin-6, and NMA each completely blocked the positive chronotropic effects of the beta-adrenoceptor agonist, isoproterenol (P < 0.01; n = 12 for each). These findings are most consistent with an inducible NO synthase-independent effect of cytokines and NMA on the chronotropic responses of neonatal cardiac myocytes to beta-adrenoceptor stimulation. This effect of cytokines and NMA on adrenergic signaling may involve a myocardial constitutive NO synthase or an NO-independent mechanism.
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PMID:Cytokines and nitric oxide synthase inhibitor as mediators of adrenergic refractoriness in cardiac myocytes. 905 50

The influence of the anti-allergy agent azelastine hydrochloride (Azeptin) on NF-kappa B activation associated with the generation of cytokines and nitric oxide (NO) was investigated in various kinds of human and mouse cells. Azeptin dose-dependently suppressed both DNA and protein synthesis in human gingival fibroblasts (HF) and also suppressed blastogenesis of human peripheral blood lymphocytes (PBL). Generation of tumor necrosis factor-alpha, interleukin 1-beta, granulocyte-macrophage colony-stimulating factor and interleukin-6 from 10(-5) M Azeptin-treated PBL and human monocytes (HM) was decreased to approximately 1/3 to 2/3 of the control levels. In parallel with the decreased cytokine generation, each cytokine mRNA was less expressed in the presence of 10(-5) M Azeptin. In addition, both inducible nitric oxide synthase-mRNA level and NO generation in mouse peritoneal macrophages were suppressed by 10(-5) M Azeptin. Being compatible with those results, Azeptin (10(-5) M) suppressed activation of NF-kappa B in PBL, HM and HF. These results appear to indicate that suppression of cytokine and NO generation by Azeptin results at least partially from the inhibition of NF-kappa B activation.
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PMID:Suppression by azelastine hydrochloride of NF-kappa B activation involved in generation of cytokines and nitric oxide. 907 48


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