UNIPROT:P05231 - FACTA Search

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Query: UNIPROT:P05231 (interleukin-6)
23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Depending on sequence, bacterial and synthetic DNAs can activate the host immune system and influence the host response to infection. The purpose of this study was to determine the abilities of various phosphorothioate oligonucleotides with cytosine-guanosine-containing motifs (CpG DNA) to activate macrophages to produce nitric oxide (NO) and prostaglandin E(2) (PGE(2)) and to induce expression of NO synthase 2 (NOS2) and cyclooxygenase 2 (COX2). As little as 0.3 microg of CpG DNA/ml increased NO and PGE(2) production in a dose- and time-dependent fashion in cells of the mouse macrophage cell line J774. NO and PGE(2) production was noted by 4 to 8 h after initiation of cultures with the CpG DNA, with the kinetics of NO production induced by CpG DNA being comparable to that induced by a combination of lipopolysaccharide and gamma interferon. CpG DNA-treated J774 cells showed enhanced expression of NOS2 and COX2 proteins as determined by immunoblotting, with the relative potencies of the CpG DNAs generally corresponding to those noted for the induction of NO and PGE(2) production as well as to those noted for the induction of interleukin-6 (IL-6), IL-12, and tumor necrosis factor. Extracts from CpG DNA-treated cells converted L-arginine to L-citrulline, but the NOS inhibitor N(G)-monomethyl-L-arginine (NMMA) inhibited this reaction. The COX2-specific inhibitor NS398 inhibited CpG DNA-induced PGE(2) production and inhibited NO production to various degrees. The NOS inhibitors NMMA, 1400W, and N-iminoethyl-L-lysine effectively blocked NO production and increased the production of PGE(2) in a dose-dependent fashion. Thus, analogues of microbial DNA (i.e., CpG DNA) activate mouse macrophage lineage cells for the expression of NOS2 and COX2, with the production of NO and that of PGE(2) occurring in an interdependent manner.
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PMID:Host response to infection: the role of CpG DNA in induction of cyclooxygenase 2 and nitric oxide synthase 2 in murine macrophages. 1170 51

Endothelial cells increase their secretion of the cytokine interleukin-6 (IL-6) during hypoxia, which then acts in an autocrine fashion to increase the permeability of cell monolayers. These responses are attenuated by antioxidants, suggesting that reactive oxygen species (ROS) participate in signaling in hypoxic endothelium. We tested whether mitochondria are responsible for these ROS in human umbilical vein endothelial cells exposed to hypoxia. Oxidation of the probe 2', 7'-dichlorodihydrofluorescein to fluorescent dichlorofluorescein or the probe dihydroethidium was used to assess oxidant signaling, whereas permeability was assessed by using transendothelial electrical resistance. Hypoxia elicited increases in dichlorofluorescein and dihydroethidium fluorescence that were abrogated by the mitochondrial electron transport (ET) inhibitors rotenone (2 micromol/L) and diphenyleneiodonium (5 micromol/L). The same ET inhibitors also attenuated hypoxia-induced increases in nuclear factor-kappaB (NF-kappaB) activation, although they did not abrogate NF-kappaB activation in response to endotoxin (lipopolysaccharide). ET inhibition also abolished the hypoxia-induced increases in IL-6 mRNA expression, hypoxia-stimulated IL-6 secretion into the media, and the hypoxia-induced increases in transendothelial electrical resistance of human umbilical vein endothelial cell monolayers. By contrast, the above responses to hypoxia were not significantly affected by treatment with the NAD(P)H oxidase inhibitor apocynin (30 micromol/L), the xanthine oxidase inhibitor allopurinol (100 micromol/L), or the NO synthase inhibitor N-nitro-L-arginine (100 micromol/L). We conclude that ROS signals originating from the mitochondrial ET chain trigger the increase in NF-kappaB activation, the transcriptional activation of IL-6, the secretion of IL-6 into the cell culture media, and the increases in endothelial permeability observed during hypoxia.
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PMID:Role of mitochondrial oxidant generation in endothelial cell responses to hypoxia. 1195 Jun 85

The immunomodulatory effect of ginsan based on the production of cytokines and the activation of macrophage was studied. Murine peritoneal macrophages (PM) on in vitro treatment with ginsan isolated from Panax ginseng induced mRNA of cytokines such as tumor necrosis factor (TNF)-alpha, interleukin-1 (IL-1)beta, interleukin-6 (IL-6) and interleukin-12 (IL-12); TNF-alpha mRNA induction was maximum within 3 h, IL-6 mRNA was gradually induced up to 24 h, and IL-1beta and IL-12 mRNA were highly induced at 24 h. IL-1beta and IL-6 protein levels also increased within 24 h in a dose-dependent manner and reached a maximum with 100 microg/ml ginsan. IL-12 was induced after 3 days and a high level of induction was detected after 4 days post treatment. Ginsan enhanced the lytic death of L929 cells through TNF-alpha activation. The mRNA expression of nitric oxide synthase (iNOS) was highly induced after 24 h treatment of ginsan, and then NO production was maximum after 48-h treatment with a low dose of 1 microg/ml. The level of iNOS mRNA induction by ginsan was slightly less than that of macrophages activating agents such as LPS plus IFN-gamma. The tumoricidal activity of macrophage cultured with ginsan on Yac-1 cells was enhanced in a dose-dependent manner; growth inhibition increased 1.6-fold with 100 microg/ml ginsan. These results suggest that ginsan exerts as an effective immunomodulator and enhances antitumor activity of macrophages.
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PMID:Induction of secretory and tumoricidal activities in peritoneal macrophages by ginsan. 1218 27

The immunologic response in atherosclerosis involves not only intrinsic cells of the artery wall, but also circulating leukocytes, lymphocytes, and macrophages. Interaction of various arms of the immune response modulates plaque development and stability, and it is conceivable that immunologic effects of some cardiovascular therapies may contribute to their mechanism of benefit. The preponderance of data has accrued with the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Statin effects, such as inhibition of T cell activation, tissue factor expression, or reduction of platelet hyperreactivity, may elicit beneficial effects in vitro and in vivo in patients with coronary artery disease. Moreover, aspirin may limit oxidation of lipoproteins and fibrinogen, and it may inhibit cytokine-induced nitric oxide synthase II expression. The hypothesis that selective inhibition of cyclooxygenase-2 (COX-2) may increase risk of myocardial infarction is controversial and may also be of questionable clinical significance. Finally, angiotensin-converting enzyme (ACE) inhibitors not only reduce proinflammatory mediators, such as interleukin-6, but also enhance the concentration of anti-inflammatory cytokines, such as interleukin-10. Because ACE is expressed at the shoulder region of atherosclerotic plaques, and ACE activity is enhanced in unstable plaques, ACE inhibition may also contribute to plaque stability. This article reviews the potential immunomodulatory potencies of aspirin, COX-2 inhibitors, statins, and ACE inhibitors as established pharmacotherapy in patients with coronary artery disease.
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PMID:Role of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors, angiotensin-converting enzyme inhibitors, cyclooxygenase-2 inhibitors, and aspirin in anti-inflammatory and immunomodulatory treatment of cardiovascular diseases. 1281 30

Porphyromonas gingivalis is a primary etiological agent of generalized severe periodontitis, and emerging data suggest the importance of reactive oxygen and nitrogen species in periodontal tissue damage, as well as in microbial killing. Since nitric oxide (NO) released from inducible NO synthase (iNOS) has been shown to possess immunomodulatory, cytotoxic, and antibacterial effects in experimental models, we challenged iNOS-deficient (iNOS(-/-)) mice with P. gingivalis by using a subcutaneous chamber model to study the specific contribution of NO to host defense during P. gingivalis infection. iNOS(-/-) mice inoculated with P. gingivalis developed skin lesions and chamber rejection with higher frequency and to a greater degree than similarly challenged C57BL/6 wild-type (WT) mice. Chamber fluid from iNOS(-/-) mice possessed significantly more P. gingivalis than that of WT mice. The immunoglobulin G responses to P. gingivalis in serum was similar in WT and iNOS(-/-) mice, and the inductions of tumor necrosis factor alpha, interleukin-1 beta and interleukin-6, and prostaglandin E(2) were comparable between the two mouse strains. Although no differences in total leukocyte counts in chamber fluids were observed between iNOS(-/-) and WT mice, the percentage of dead polymorphonuclear leukocytes (PMNs) was significantly greater in iNOS(-/-) mouse chamber fluids than that of WT samples. Interestingly, casein-elicited PMNs from iNOS(-/-) mice released more superoxide than did WT PMNs when stimulated with P. gingivalis. These results indicate that modulation of superoxide levels is a mechanism by which NO influences PMN function and that NO is an important element of the host defense against P. gingivalis.
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PMID:Mice lacking inducible nitric oxide synthase demonstrate impaired killing of Porphyromonas gingivalis. 1293 33

We describe the characterization of a spontaneously transformed chicken monocytic cell line that developed as a single colony of cells in a heterophil culture that was inadvertently left in the incubator over a period of 25 days. These cells, hitherto named HTC, grow efficiently at both 37 or 41 degrees C in culture medium containing either 5% FBS or 2% chicken serum. The HTC cells are acid phosphatase positive, show expressions of both class I and class II major histocompatibility complex (MHC), CD44, K1, and K55 cell surface antigens, and engulf latex beads, produce nitrite and interleukin-6 on stimulation with bacterial lipopolysaccharide (LPS). Treatment with phorbol myristate acetate (PMA) induces respiratory burst in HTC cells and the secretion of matrix metalloproteinase (MMP) into culture medium. Using gene-specific primers and reverse transcriptase-polymerase chain reaction (RT-PCR), the presence of mRNA trancripts for interferon-gamma (IFN-gamma), interleukin-1 (IL-1), interleukin-6 (IL-6), nitric oxide synthase (NOS), matrix metalloproteinase-2 (MMP-2), and transforming growth factor-beta (TGF-beta) were detected. Lipopolysaccharide (LPS) treatment of HTC cells modulated IL-1, IL-6, IFN-gamma, NOS mRNA levels as detected by RT-PCR analyses. Using different avian tumor virus gene-specific primers and PCR, the HTC cells were positive for the presence of avian leukosis virus (ALV) and Marek's disease virus (MDV) but negative for reticuloendothelial virus (REV), chicken infectious anemia virus (CIAV), and herpes virus of turkeys (HVT). The production of ALV antigens by HTC cells was further confirmed using p27 gag protein ELISA. Collectively, these results show that the HTC cells belong to myeloid/macrophage lineage and were likely transformed by ALV and MDV but retain many interesting and useful biological activities.
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PMID:Characterization of a spontaneously transformed chicken mononuclear cell line. 1452 38

This article is a review of our experimental results regarding the physiological statuses and roles of chemical mediators in tourniquet shock, and a novel phenomenon, modulation reflex, that is commonly observed in this shock model is discussed. In a rabbit with a tourniquet applied to a hind limb for 24 hrs, blood pressure (BP) gradually falls after release of the tourniquet, but the decline in BP stops when a tourniquet is again applied to the hind limb, indicating that shock mediators are attributed to the hind limb. The levels of dipeptides (anserine and carnosine) and lysosomes in blood samples as well as the levels of leukotrienes (LTD4 and LTE4) in blood and muscle samples from rabbits in tourniquet shock were elevated. However, injection of a large amount of a dipeptide into an ear vein of a rabbit did not reduce BP, suggesting that both peptides may not be directly related with reduction in BP of rabbits in tourniquet shock. Injection of a platelet-activating factor (PAF) antagonist into an ear vein resulted in slight elevation of BP and the elevated level was maintained for about 1 to 4 hrs during the period of decline in BP in tourniquet shock. As for interleukin-6 (IL-6), IL-6-deficient mice at young ages have a significantly greater blood volume than do wild-type mice without concomitant changes in body composition. Therefore, the role for IL-6 in the regulation of peripheral circulation may be to elevate, not reduce BP. In mice in tourniquet shock, superoxide (O2-) production is observed in skeletal muscle cells and these cells correspond to mitochondria-rich cells. However, RT-PCR of muscle samples showed no significant nitric oxide synthase (NOS) mRNA expression after tourniquet release. Pretreatment with NOS inhibitors before tourniquet release reduced O2- production in the skeletal muscle. These results indicate that O2- produced in muscle subjected to ischemia/repefusion may be involved in shock. As for changes in mRNA expression patterns of pro-inflammatory cytokines and nerve growth factors in blood samples from rats in tourniquet shock, up-regulation of M-CSF mRNA began at 2 h after tourniquet application and was short-lived. The level of ATF-3 mRNA had increased at 1 h and NGF mRNA gradually increased and reached a significantly high level at 4 h after tourniquet application. These results indicate that the transient mRNA expressions probably trigger secondary events that may be beneficial to wound repair and regeneration. In the early stage of tourniquet shock, the levels of IL-6 mRNA in the liver and kidneys of rats increased progressively and significantly, and the levels of iNOS mRNA in the kidneys increased. These findings suggest that that humoral and/or cellular mediators produced locally in the hind limb are responsible for remote organ injuries. Thus, these mediators, interacting each other, may contribute to the progress of shock. We have also found a novel phenomenon in tourniquet shock using rabbits. When a tourniquet is applied to the upper hind limb of a rabbit for 24 hrs, and pressure is applied to the femoral medial area immediately after tourniquet release, a reflex of decrease in blood pressure and decrease in heart rate, which last for a short period, is usually observed. This reflex is mediated through the ipsilateral femoral nerves, central nervous system and vagal nerves. Since the modulation reflex may be due to peripheral nerve injury, we investigated morphological and molecular changes in sciatic nerves and dorsal root ganglion (DRG) neurons in rats after tourniquet application. At 4 hr after tourniquet application, light microscopic examination showed only degeneration of the tourniquet segment in the sciatic nerve but no morphological changes in the DRG, while electron microscopic examination revealed mitochondrial swelling in some DRG neurons on the tourniquet-applied side and calcium deposition in these swollen mitochondria. These findings suggest that peripheral nerve injury induced a large amount of calcium influx into neuronal cell somas and that excess amounts of calcium-influx into neurons resulted in mitochondial swelling. Results of mRNA level analyses showed NGF mRNA expression followed by NGF protein expression in Schwann cells of the ipsilateral DRGs at 4 h after tourniquet application but not in the contralateral or control DRGs. Similarly, significantly high nNOS and iNOS mRNA levels were observed in the ipsilateral DRGs at 4 h, and expressions of nNOS and iNOS proteins were detected in the ganglion of the ipsilateral DRG. In addition, the TNF-alpha mRNA levels were significantly increased in the ipsilateral DRGs at 1 h after tourniquet application, indicating that TNF-alpha was activated in the early stage of nerve injury and then induced iNOS mRNA expression. Large amounts of nitric oxide (NO) produced by iNOS might result in damage to the host cells, and an overdose of NO might induce apoptosis and eliminate damaged cells during the early stage of nerve injury.
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PMID:[Novel findings from an animal tourniquet shock model]. 1457 64

Clara cell 10-kDa protein (CC10) is a major component of bronchoalveolar lavage fluid and is suggested to be a natural regulator of airway inflammation, possibly through its effects on the proinflammatory enzyme(s), phospholipase A2. We examined the effect of recombinant human (rh) CC10 on endotoxin-induced airway contraction and cytokine release in isolated perfused rat lungs. We found that rhCC10 added to the lung perfusate abolished the endotoxin-induced airway contraction, and that it inhibited both the release of interleukin-1 beta and interleukin-6 into the lung perfusate and the release of tumor necrosis factor-alpha into the pulmonary lavage fluid. By contrast, the levels of interferon-gamma were unaffected by CC10 administration. Rutin, a phospholipase A2 inhibitor, and N omega-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, also attenuated the contraction induced by endotoxin. These findings demonstrate that rhCC10 inhibits endotoxin-induced airway contraction and the release of proinflammatory cytokines (interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha) in isolated perfused rat lungs. The results also indicate that phospholipase A2 and nitric oxide are involved in the airway contraction in this model, possibly through their influence on the production of eicosanoids.
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PMID:Clara cell 10-KDA protein inhibits endotoxin-induced airway contraction in isolated perfused rat lungs. 1471 Apr 38

The utility of C-reactive protein (CRP) as an independent risk factor for vascular events may be attributable, at least in part, to a direct adverse impact of CRP on endothelial function. In particular, modestly elevated concentrations of CRP have been shown to decrease the expression of the endothelial isoform of nitric oxide synthase (eNOS) in endothelial cells; the implication of this for vascular health is evident. Strategies for decreasing elevated CRP include administration of statins, thiazolidinediones, and metformin; moderate alcohol consumption and appropriate weight loss are also helpful in this regard. Metformin's antidiabetic efficacy is now known to reflect activation of AMP-activated kinase (AMPK); AMPK can stimulate eNOS, which is expressed in hepatocytes. A recent study shows that nitric oxide suppresses the activation of Stat3 by interleukin-6 in hepatocytes; Stat3 is crucial for the IL-6-mediated induction of CRP and various other acute phase reactants. Thus, it is proposed that metformin--or AMPK---inhibits hepatic CRP production by boosting hepatic nitric oxide synthesis, which in turn impedes Stat3 activation and CRP transcription. This hypothesis should be readily testable in cultured hepatocytes. Although the impact of metformin on plasma IL-6 levels has not been reported, the possibility that AMPK activation could influence adipocyte secretion of this cytokine also merits scrutiny.
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PMID:AMPK activation may suppress hepatic production of C-reactive protein by stimulating nitric oxide synthase. 1523 98

It has become clear that spinal cord glia (microglia and astrocytes) importantly contribute to the creation of exaggerated pain responses. One model used to study this is peri-spinal (intrathecal, i.t.) administration of gp120, an envelope protein of HIV-1 known to activate glia. Previous studies demonstrated that i.t. gp120 produces pain facilitation via the release of glial proinflammatory cytokines. The present series of studies tested whether spinal nitric oxide (NO) contributes to i.t. gp120-induced mechanical allodynia and, if so, what effect NO has on spinal proinflammatory cytokines. gp120 stimulation of acutely isolated lumbar dorsal spinal cords released NO as well as proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta (IL1), interleukin-6 (IL6)), thus identifying NO as a candidate mediator of gp120-induced behavioral effects. Behaviorally, identical effects were observed when gp120-induced mechanical allodynia was challenged by i.t. pre-treatment with either a broad-spectrum nitric oxide synthase (NOS) inhibitor (L-NAME) or 7-NINA, a selective inhibitor of NOS type-I (nNOS). Both abolished gp120-induced mechanical allodynia. While the literature pre-dominantly documents that proinflammatory cytokines stimulate the production of NO rather than the reverse, here we show that gp120-induced NO increases proinflammatory cytokine mRNA levels (RT-PCR) and both protein expression and protein release (serial ELISA). Furthermore, gp120 increases mRNA for IL1 converting enzyme and matrix metalloproteinase-9, enzymes responsible for activation and release of proinflammatory cytokines.
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PMID:HIV-1 gp120 stimulates proinflammatory cytokine-mediated pain facilitation via activation of nitric oxide synthase-I (nNOS). 1528 92

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