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)

Administration of selective and nonselective cyclooxygenase (COX)-2 inhibitors to rheumatoid arthritis patients taking low doses of acetylsalicylic acid (ASA) for cardiovascular prevention associates with increased risk of gastrointestinal bleeding. The present study was undertaken to investigate whether administration of HCT-3012 [(S)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid 4-(nitrooxy)butyl ester], a nitric oxide (NO)-releasing derivative of naproxen, exacerbates gastric mucosal injury in arthritic rats administered low doses of ASA. Our results demonstrated that while treating arthritic rats with a dose of 30 mg/kg/day ASA causes detectable mucosal injury, but had no effect on arthritis score and interleukin-6 plasma levels, coadministration of naproxen (10 mg/kg/day) and celecoxib (30 mg/kg/day), in combination with ASA from day 7 to day 21, attenuates arthritis development (P <0.01 versus arthritis alone), but markedly enhanced gastric mucosal damage caused by ASA (P <0.01 versus ASA alone). In contrast, coadministration of HCT-3012 (15 mg/kg/day) significantly attenuated arthritis development, because HCT-3012 was equally or more effective than naproxen and celecoxib in attenuating local and systemic inflammation (P >0.001 versus arthritis) without exacerbating gastric mucosal injury caused by ASA. Arthritis development associates with gastric COX-2 induction, mRNA and protein, and enhanced gastric prostaglandin E2 (PGE2) synthesis (P <0.01 versus control rats). Although all treatments, including celecoxib, were effective in reducing gastric PGE2 synthesis, administering arthritic rats with ASA resulted in a significant increase in gastric content of aspirin-triggered lipoxin (ATL), a COX-2-derived lipid mediator that regulates proinflammatory responses at the neutrophils/endothelial interface. Administering arthritic rats with naproxen and celecoxib abrogates ATL formation induced by ASA although enhanced neutrophils accumulate into the gastric mucosa (P <0.01 versus ASA alone). In contrast, whereas HCT-3012 inhibited ATL formation, it did not increase neutrophil recruitment into the gastric microcirculation. Collectively, these data indicate that HCT-3012 derived from NO has the potential to compensate for inhibition of PGE2 and ATL and to protect the gastric mucosa by limiting the recruitment of neutrophils. These data suggest that HCT-3012 might be a safer alternative to nonsteroidal anti-inflammatory drugs and coxibs in rheumatic patients that take low doses of ASA.
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PMID:Nitric oxide (NO)-releasing naproxen (HCT-3012 [(S)-6-methoxy-alpha-methyl-2-naphthaleneacetic Acid 4-(nitrooxy)butyl ester]) interactions with aspirin in gastric mucosa of arthritic rats reveal a role for aspirin-triggered lipoxin, prostaglandins, and NO in gastric protection. 1938 39

The aim of the study was to characterize the in vitro effect of non-steroidal anti-inflammatory drugs (NSAIDs) on the production of pro-inflammatory cytokines in a human whole blood assay. Whole blood samples were pre-incubated with acetylsalicylic acid, indomethacin, selective cyclooxygenase (COX)-1 inhibitor (SC-560), COX-2 inhibitor (NS-398) or prostaglandin E2 (PGE2) before stimulation with lipopolysaccharide (LPS). Pro-inflammatory and anti-inflammatory cytokines were determined directly at the cell level with the help of flow cytometry and/or in the plasma supernatant with the help of ELISA. High doses of acetylsalicylic acid were needed to inhibit pro-inflammatory cytokine production. In contrast, low-to-moderate doses induced a modestly enhanced production of pro-inflammatory cytokines. Moreover, indomethacin was demonstrated to increase the expression of interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) in a dose-dependent fashion. Upon addition of PGE2, however, LPS-induced IL-6 and TNF-alpha production was suppressed regardless of indomethacin presence. Interestingly, selective COX-2 inhibition (NS-398), but not selective COX-1 inhibition (SC-560), exerted a stimulatory effect on the expression of pro-inflammatory cytokines. These data emphasize that the immunomodulating effects of NSAIDs in whole blood are dose-dependent. Furthermore, the induction of pro-inflammatory cytokine expression by NSAIDs is potentially mediated by COX-2 inhibition. Although NSAIDs are successfully used in clinical practice for their net anti-inflammatory properties, our observations may contribute to the understanding of side effects induced by NSAIDs and selective COX-2 inhibitors.
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PMID:Dose-dependent immunomodulatory effects of acetylsalicylic acid and indomethacin in human whole blood: potential role of cyclooxygenase-2 inhibition. 1537 66

The purpose of this investigation was to evaluate the dose-dependent effects of docosahexaenoic acid (DHA) on deoxynivalenol (DON)-induced IgA nephropathy in mice and their relation to proinflammatory gene expression and mitogen-activated protein kinase (MAPK) activation. Consumption of a modified AIN-93G diet containing 1, 5, and 30 g/kg DHA resulted in dose-dependent increases of DHA in liver phospholipids with concomitant decreases in arachidonic acid compared with control diets. DHA dose dependently inhibited increases in serum IgA and IgA immune complexes (IC) as well as IgA deposition in the kidney in DON-fed mice; the 30 g/kg DHA diet had the earliest detectable effects and maximal efficacy. Both splenic interleukin-6 (IL-6) mRNA and heterogeneous nuclear RNA (hnRNA), an indicator of IL-6 transcription, were significantly reduced in DON-fed mice that consumed 5 and 30 g/kg DHA; a similar reduction was observed for cyclooxygenase (COX-2) mRNA. In a subsequent study, acute DON exposure (25 mg/kg body weight) induced splenic IL-6 mRNA and hnRNA as well as COX-2 mRNA in mice fed the control diet, whereas induction of both RNA species was significantly inhibited in mice fed 30 g/kg DHA. These latter inhibitory effects corresponded to a reduction in DON-induced phosphorylation of p38, extracellular-signal related kinase 1/2, and c-Jun N-terminal kinase 1/2 MAPKs in the spleen. Taken together, the results indicate that DHA dose-dependently inhibited DON-induced IgA dysregulation and nephropathy, and that impairment of MAPK activation and expression of COX-2 and IL-6 are potential critical upstream mechanisms.
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PMID:Docosahexaenoic acid attenuates mycotoxin-induced immunoglobulin a nephropathy, interleukin-6 transcription, and mitogen-activated protein kinase phosphorylation in mice. 1557 35

Low-dose aspirin (acetylsalicylic acid) is used as prophylaxis against cardiovascular diseases. The effect of aspirin on inflammation and oxidative stress, processes known to be involved in cardiovascular diseases, are not fully known. The cyclooxygenase(COX)-mediated inflammatory indicator prostaglandin F2alpha (PGF2alpha) (15-keto-dihydro-PGF2alpha), cytokine-mediated inflammatory indicators (interleukin-6, high-sensitivity C-reactive protein, serum amyloid A protein), and oxidative stress indicators (8-iso-PGF2alpha, tocopherols) were quantified in men with daily 75 mg of aspirin (n=175) and control men (n=464), all of age 77, in a cross-sectional study. Men treated with aspirin had decreased levels of urinary 15-keto-dihydro-PGF2alpha than controls (P<0.01), independent of possible cardiovascular risk factors. Aspirin-treated men had increased levels of alpha-tocopherol than controls (P<0.05). This is the first study to indicate that low-dose aspirin treatment is associated with decreased levels of PGF2alpha. This observation suggests a possible COX-mediated anti-inflammatory effect of low-dose aspirin, which should be further confirmed by intervention studies.
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PMID:Cyclooxygenase-mediated prostaglandin F2alpha is decreased in an elderly population treated with low-dose aspirin. 1576 33

Several studies have demonstrated that nonsteroidal anti-inflammatory drugs, such as acetylsalicylic acid (ASA), can have inhibitory or enhancing effects on inflammatory cell function. These effects seem independent of cyclooxygenase activity and prostaglandin synthesis inhibition. Here, we examined the effect of ASA on bone marrow-derived mast cells in more detail. ASA blocked the expression of cyclooxygenase-2, the production of tumor necrosis factor-alpha and interleukin-6, and the release of granule mediators from mast cells in a concentration-dependent fashion. Concomitantly, ASA inhibited nuclear factor (NF)-kappaB activity, as well as the phosphorylation and breakdown of the inhibitory protein IkappaB-alpha. We thus propose that the anti-inflammatory effects of ASA in mast cells are due to suppression of IkappaB kinase activity, thereby inhibiting subsequent phosphorylation and degradation of IkappaB-alpha, activation of NF-kappaB, and transcription of proinflammatory cytokines. The inhibition of BMMC degranulation was independent of NF-kappaB activation, however. Interestingly, the expression of cyclooxygenase-2 was not inhibited at 1mM ASA, but was even enhanced significantly. The latter might contribute to the adverse effects of ASA in ASA-sensitive asthmatics.
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PMID:Dual effects of acetylsalicylic acid on mast cell degranulation, expression of cyclooxygenase-2 and release of pro-inflammatory cytokines. 1576 41

The pro-inflammatory cytokine interleukin-6 (IL-6) together with its soluble receptor (sIL-6R) induces and maintains thermal hyperalgesia. It facilitates the heat-induced release of calcitonin gene-related peptide from rat cutaneous nociceptors in vivo and in vitro. Here we report that exposure of nociceptive neurons to the IL-6-sIL-6R complex or the gp130-stimulating designer IL-6-sIL-6R fusion protein Hyper-IL-6 (HIL-6) resulted in a potentiation of heat-activated inward currents (I(heat)) and a shift of activation thresholds towards lower temperatures without affecting intracellular calcium levels. The Janus tyrosine kinase inhibitor AG490, the selective protein kinase C (PKC) inhibitor, bisindolylmaleimide 1 (BIM1), as well as rottlerin, a selective blocker of the PKCdelta isoform, but not the cyclooxygenase inhibitor indomethacin, effectively reduced the effect. Reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization revealed expression of mRNA for the signal-transducing beta subunit of the receptor gp130 in neuronal somata, rather than satellite cells in rat dorsal root ganglia. Together, the results suggest that IL-6-sIL-6R acts directly on sensory neurons. It increases their susceptibility to noxious heat via the gp130/Jak/PKCdelta signalling pathway.
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PMID:Fast modulation of heat-activated ionic current by proinflammatory interleukin 6 in rat sensory neurons. 1581 18

The underlying mechanisms by which smoking induces cardiovascular diseases are largely unknown. The effect of smoking status on the cyclooxygenase (COX)-mediated inflammatory indicator prostaglandin F(2alpha) (PGF(2alpha)) has never been studied. Associations of cytokines and antioxidants and smoking status, have shown conflicting results. Urinary 15-keto-dihydro-PGF(2alpha) (a major metabolite of PGF(2alpha)), serum interleukin-6 (IL-6) and high sensitivity C-reactive protein (hsCRP), serum amyloid protein A (SAA), urinary 8-iso-PGF(2alpha) (an F(2)-isoprostane, indicator of oxidative stress), and serum alpha-tocopherol were quantified in a population-based sample (n = 642) of 77-year old men without diabetes. Fifty-five men were current smokers and 391 former smokers. Inflammatory indicators were increased in current smokers (15-keto-dihydro-PGF(2alpha), P < 0.001; IL-6, P = 0.01) than non-smokers. 8-iso-PGF(2alpha) was increased (P < 0.01) and alpha-tocopherol reduced (P < 0.001) in current smokers. Further, former smokers had increased formation of 15-keto-dihydro-PGF(2alpha), IL-6 and 8-iso-PGF(2alpha) compared non-smokers. This is the first study to show that smokers have increased PGF(2alpha) formation, thus enhanced COX-mediated inflammation, in addition to elevated levels of cytokines and isoprostanes. Subclinical COX- and cytokine-mediated inflammation and oxidative stress are ongoing processes not only in active smokers but also in former smokers which may contribute to the accelerated atherosclerosis associated with smoking.
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PMID:Active smoking and a history of smoking are associated with enhanced prostaglandin F(2alpha), interleukin-6 and F2-isoprostane formation in elderly men. 1593 73

Low concentrations of selenium (Se) predict mortality and cardiovascular diseases in some populations. The effect of Se on in vivo indicators of oxidative stress and inflammation, two important features of atherosclerosis, in human populations is largely unexplored. This study investigated the longitudinal association between serum selenium (s-Se) and a golden standard indicator of oxidative stress in vivo (8-iso-prostaglandin F2alpha, a major F2-isoprostane), an indicator of cyclooxygenase (COX)-mediated inflammation (prostaglandin F2alpha), high sensitive C-reactive protein (hsCRP), interleukin-6 (IL-6) and serum amyloid A protein (SAA) in a follow-up study of 27 years. The s-Se was measured in 615 Swedish men at 50 years of age in a health investigation. The status of oxidative stress and inflammation was evaluated in a re-investigation 27 years later by quantification of urinary 8-iso-PGF2alpha and 15-keto-dihydro-PGF2alpha (a major metabolite of PGF2alpha) and serum hsCRP, SAA and IL-6. Men in the highest quartile of s-Se at age 50 had decreased levels of 8-iso-PGF2alpha compared to all lower quartiles and decreased levels of PGF2alpha compared to all lower quartiles at follow-up. These associations were independent of BMI, diabetes, hyperlipidemia, hypertension, smoking, alpha-tocopherol and beta-carotene at baseline. The s-Se was not associated with hsCRP, SAA or IL-6 at follow-up. In conclusion, high concentrations of s-Se predict reduced levels of oxidative stress and subclinical COX-mediated (but not cytokine-mediated) inflammation in a male population. The associations between Se, oxidative stress and inflammation, respectively, might be related to the proposed cardiovascular protective property of Se.
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PMID:Serum selenium predicts levels of F2-isoprostanes and prostaglandin F2alpha in a 27 year follow-up study of Swedish men. 1603 56

Lipopolysaccharide (LPS) has been known to induce endotoxin shock via production of inflammatory modulators such as tumor necrosis factor alpha (TNF-alpha), or nitric oxide (NO). In this study, we have examined the effect of naringin (NG), one of the flavonoids, on LPS-induced endotoxin shock in mice and NO production in RAW 264.7 macrophages. For intraperitoneal (i.p., 20 mg/kg) injection of LPS at 48 h, the survival rate of mice administered with LPS alone (n=10) or pretreated with NG at 10, 30 and 60 mg/kg (i.p.) group (n=10) was 0% or 10%, 50% and 70%, respectively. NG dose-dependently suppressed LPS-induced production of TNF-alpha. LPS-induced production of NO at 6 h (125.89+/-16.35 microM), as measured by nitrite formation, was significantly reduced by NG at 30 or 60 mg/kg for 49.49+/-4.81 or 27.91+/-1.81 microM (P<0.01 vs. LPS alone), respectively. To further examine the mechanism by which NG suppresses LPS-induced endotoxin shock, we used an in vitro model, RAW 264.7 mouse macrophage cells. NG (1 mM) suppressed LPS (0.01, 0.1 or 1 microg/ml)-induced production of NO and the expression of inflammatory gene products such as inducible NO synthase (iNOS), TNF-alpha, inducible cyclooxygenase (COX-2) and interleukin-6 (IL-6) as determined by RT-PCR assay. NG was found to have blocked the LPS-induced transcriptional activity of NF-kappaB in electrophoretic mobility shift assay and reporter assay. These findings suggest that suppression of the LPS-induced mortality and production of NO by NG is due to inhibition of the activation of NF-kappaB.
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PMID:Inhibitory effect of naringin on lipopolysaccharide (LPS)-induced endotoxin shock in mice and nitric oxide production in RAW 264.7 macrophages. 1613

In response to endogenous and exogenous stimuli, macrophages are activated to produce a cocktail of proinflammatory and anti-apoptotic mediators, thereby participating in the processes of inflammation-associated oncogenesis. Cereals, including corn and rice, have biological potentials to synthesize self-protective chemicals in order to repel the invasion of microorganisms and insects. We examined the suppressive effects of several fatty acids, including a new class of lipoxygenase metabolites of linoleic acid (LA) found in cereals, namely (+/-)-9-hydroxy-trans,cis-10,12-octadecadienoic acid (9-HOA from rice), (+/-)-13-hydroxy-10-oxo-trans-11-octadecenoic acid (13-HOA from corn), and (+/-)-10-oxo-trans-11-octadecen-13-olide (10-ODO from corn), on lipopolysaccharide (LPS)-induced mRNA expression of proinflammatory mediators in RAW264.7 murine macrophages. Each metabolite exhibited a suppressive activity toward nitrite production than LA, octadeca-9Z,11E-dienoic acid (a conjugated LA), and 13S-hydroxyoctadeca-9Z,11E-dienoic acid. LPS-up-regulated mRNA expression of inducible nitric oxide synthase, cyclooxygenase (COX)-2, interleukin-6, and toll-like receptor-2, -4, and -9 was also markedly attenuated without affecting the expression levels of several constitutive genes, including COX-1, as detected by reverse transcription-polymerase chain reactions. In addition, Western blot and luciferase reporter assay results showed that 13-HOA suppressed the phosphorylation of mitogen-activated protein kinases (extracellular signal-regulated kinasel/2, c-Jun N-terminal kinasel/2, p38 mitogen-activated protein kinase), and Akt (Ser473), and also attenuated degradation of inhibitor kappaB, nuclear translocation of nuclear factor kappaB (NFkappaB), and the transcriptional activities of NFkappaB and activator protein-1, both of which have essential roles in the transcription of numerous proinflammatory and oncogenic genes. In contrast, 13-HOA did not serve as a ligand for peroxisome proliferator-activated receptor-gamma. Based on our findings, we propose that 13-HOA, a functionally novel LA-derivative, is a promising agent for anti-inflammatory and chemopreventive strategies with reasonable molecular mechanisms.
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PMID:New class of linoleic acid metabolites biosynthesized by corn and rice lipoxygenases: suppression of proinflammatory mediator expression via attenuation of MAPK- and Akt-, but not PPARgamma-, dependent pathways in stimulated macrophages. 1614 12


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