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)

This study was undertaken to evaluate the effect of a cyclooxygenase inhibitor, ibuprofen, at various time intervals in a live Escherichia coli model of canine septic shock. Group I (control) animals (n = 5) received a LD100 dose of 10(9) live E. coli per kilogram were given no further treatment. Group II animals (n = 5) received a 10 mg/kg bolus of ibuprofen 10 min prior to bacterial infusion. Group III animals (n = 5) received ibuprofen 15 min after the bacterial infusion. Statistical analysis revealed the following: Group II animals had significantly higher MABP and significantly lower levels of serum fluorescent products (superoxide radical activity), plasma thromboxane B2, prostaglandin E2, and endotoxin levels compared to Group I animals (P less than 0.05). Plasma levels of tumor necrosis factor (TNF) and interleukin-6 (IL-6) were significantly elevated (P less than 0.05) from baseline in all animals (Groups I, II, and III), but ibuprofen treatment failed to either increase or decrease these levels. This study demonstrates that ibuprofen treatment can significantly reverse the deleterious hemodynamic and metabolic effects commonly seen in live E. coli septic shock without depressing the endogenous production of TNF or IL-6. These data support the hypothesis that sepsis initiates a cascade of mediators with the cytokines TNF and IL-6 being proximal events which in turn stimulate the next level, with ibuprofen probably exerting its inhibitory effect distal to this point in the cascade.
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PMID:Ibuprofen intervention in canine septic shock: reduction of pathophysiology without decreased cytokines. 132 83

We recently reported that human recombinant interleukin-6 (hrIL-6) microinjected into the preoptic area (POA) of guinea pigs induced fever at high doses, suggesting that IL-6 may be another endogenous pyrogen. This study was undertaken to determine whether hrIL-6 affects the single-unit activity of thermosensitive and thermally insensitive neurons in hypothalamic tissue slices and whether indomethacin (Indo) or naloxone (Nal), a cyclooxygenase inhibitor and a mu-opioid receptor antagonist, respectively, influences the effects of hrIL-6 on those neurons. hrIL-6 (2 x 10(3)-8 x 10(3) U/ml) depressed the activity in 50 (83%) of 60 warm-sensitive (W) neurons and excited all 4 cold-sensitive (C) neurons found. It had no effect, however, on 14 (48%) of 29 thermally insensitive (I) neurons, albeit 7 and 8 I neurons decreased and increased their firing rates, respectively. Indo (0.05-1 mg/ml) blocked the effect of hrIL-6 on 22 of 24 W neurons and 2 C neurons tested. Nal(0.1-1 mg/ml) blocked or reduced the effect of hrIL-6 on 21 of 25 W neurons and 1 C neuron recorded. These drugs induced no neuronal response per se. Nal at 2-5 mg/ml, which increased the activity of four W neurons by itself, reversed their depressed response to hrIL-6. These results support the possibility that IL-6-induced fevers may be mediated through an effect on thermosensitive neurons in the POA and that opioids and prostaglandin E may both be involved in this process.
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PMID:Hypothalamic neuronal responses to interleukin-6 in tissue slices: effects of indomethacin and naloxone. 150 50

We have demonstrated that centrally administered interleukin-6 (IL-6) stimulates adrenocorticotropin (ACTH) secretion by a direct effect on corticotropin-releasing factor (CRF) release from the hypothalamus. Since metabolites of the arachidonic acid cascade (AAC) have been implicated in mediating actions of cytokines in different tissues and some AAC inhibitors were able to block pyrogenic effects of cytokines and suppress IL-1-induced ACTH secretion, we decided to examine the mechanism of IL-6 action on CRF release in vitro. After a 60-min preincubation in Krebs-Ringer bicarbonate buffer, medial basal hypothalami (MBH) were preincubated for 30 min with dexamethasone (DEX), a phospholipase A2 (PLA2) inhibitor, to block arachidonic acid (AA) formation, or with inhibitors of AA metabolism: a cyclooxygenase inhibitor--indomethacin (IND); a lipoxygenase inhibitor--5,8,11-eicosatriynoic acid (ETI), and an epoxygenase inhibitor--clotrimazole (CLO). Then, the medium was discarded and MBH were incubated with medium or the above compounds and/or IL-6 for 30 min, and CRF release into the incubation medium was measured by radioimmunoassay. As reported previously, 10(-13) M IL-6 increased CRF release, which was significantly suppressed by DEX in a dose-dependent manner. The suppression was already highly significant at a concentration of 10(-11) M DEX and became maximal at 10(-7) M, at which concentration CRF release was no longer stimulated by IL-6. The response to IL-6 was completely blocked at the highest DEX concentration evaluated (10(-5) M). CLO also suppressed IL-6-induced CRF release with a minimal effective dose of 10(-9) M. Suppression was complete at 10(-7) and 10(-5) M.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Involvement of arachidonic acid cascade pathways in interleukin-6-stimulated corticotropin-releasing factor release in vitro. 163 May 86

Following incubation of murine epidermis in medium containing either interleukin-2 or interleukin-6, there is significant upregulation in the density of Ia+ epidermal Langerhans cells (to 159% and 175% of control, respectively). This cytokine-induced upregulation is abrogated by either rabbit or human IgG due to triggering of Fc gamma receptors. In contrast, human IgA does not inhibit the effect of interleukin-2 or interleukin-6. Using different isotypes of murine IgG, we have demonstrated that all subclasses are capable of inhibiting the cytokine-induced enhancement of Ia antigen, although IgG1 and IgG2b must be heat aggregated to be effective. The IgG-mediated events are dependent on prostaglandin synthesis because they can be blocked by the cyclooxygenase inhibitor indomethacin, 10 micrograms/ml. The responsible PG appears to be PGD2; in contrast to its known inhibitory effect on macrophages, PGE2 does not inhibit the upregulation of Ia antigen on Langerhans cells. In addition, these IgG-mediated events are dependent upon the generation of cAMP because they can be blocked by the adenylate cyclase inhibitor 2',5'-dideoxyadenosine, 1 mM. Despite the apparently central role of PGD2 and cAMP in this process, triggering of the Fc gamma R by different isotypes of IgG blocks upregulation of Ia via at least two different pathways. The inhibition caused by aggregated IgG1 or IgG2b, which bind to Fc gamma RII on Langerhans cells, is abrogated by para-bromophenacylbromide, an inhibitor of phospholipase A2. In contrast, the inhibition caused by monomeric IgG2a, which binds to Fc gamma RI most likely on keratinocytes, or monomeric IgG3, which probably binds to this same Fc gamma RI, is abrogated by staurosporine, an inhibitor of protein kinase C, as well as by W7, a calmodulin antagonist. Finally, 1,2 dioctanoyl-rac-glycerol, an activator of protein kinase C, mimics the Ig-mediated events. Based on these findings, as well as studies using monoclonal antibodies to the murine Fc gamma receptors I and II, we conclude that, as is the case in murine macrophages, triggering of an epidermal Fc gamma RI, most likely on keratinocytes, results in the generation of cAMP via a Ca(++)-dependent protein kinase C pathway, whereas triggering of an epidermal Fc gamma RII, most likely on Langerhans cells, results in the elevation of cAMP via a phospholipase A2-mediated pathway. In contrast to the situation for macrophages, PGD2 is a vital intermediate in both pathways, perhaps because Langerhans cells have receptors for only this prostaglandin.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effect of triggering epidermal Fc gamma receptors on the interleukin-2- and interleukin-6-induced upregulation of Ia antigen expression by murine epidermal Langerhans cells: the role of prostaglandins and cAMP. 165 69

Fever induced by endogenous as well as exogenous pyrogens is often prevented by cyclooxygenase inhibitors; endogenous pyrogens stimulate prostaglandin E2 (PGE2) in or near the thermoregulatory centers of the brain. The cytokines, interleukin-1 (IL-1) and tumor necrosis factor (TNF), are two pyrogens which stimulate brain PGE2 formation during fever and also increase PGE2 synthesis in human mononuclear cells in vitro. In the present study, we examined whether interleukin-6 (IL-6) stimulates PGE2 formation in a manner similar to IL-1 and TNF. Both glycosylated and non-glycosylated forms of recombinant human IL-6 were tested. Following intravenous injection into rabbits, the glycosylated IL-6 was more pyrogenic than the non-glycosylated form and there was no evidence of synergy in the production of fever when IL-6 and IL-1 were given simultaneously. IL-6 fever was blocked by prior administration of the cyclooxygenase inhibitor ibuprofen. IL-6 was also pyrogenic in the cat by either the systemic or the intraventricular route. However, in both species, IL-6 was less effective than IL-1 beta. When given intraventricularly to cats, IL-6 produced an increase in PGE2 levels of the cerebrospinal fluid in parallel with the rise in body temperature. In the latter respect, IL-6 imitated IL-1 beta; however, IL-6 from 0.15-15 micrograms/ml did not increase mononuclear cell PGE2 production in vitro whereas IL-1 beta induced 20-30-fold increases in PGE2 at 100 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interleukin-6 as an endogenous pyrogen: induction of prostaglandin E2 in brain but not in peripheral blood mononuclear cells. 177 38

Intracerebroventricular (i.c.v.) injection of human recombinant interleukin-6 (IL-6; 20-100 ng) caused significant increases in colonic temperature and resting oxygen consumption (VO2) in conscious rats. These effects were prevented by pretreatment with a cyclooxygenase inhibitor (flurbiprofen, 1 mg/kg, i.p.) or a corticotrophin-releasing factor antagonist (alpha-helical CRF9-41, 25 micrograms, i.c.v.). Higher doses of IL-6 (i.c.v.) caused only small changes in VO2 and temperature, and very high doses given intravenously (i.v.) (4 micrograms/kg) were required to stimulate these parameters. Central injection of anti-rat IL-6 antibody inhibited the effects of interleukin-1 beta (i.c.v.) or endotoxin injection (i.p.) on colonic temperature and VO2 in conscious rats. These data indicate that IL-6 is an important endogenous pyrogen that acts within the central nervous system.
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PMID:Interleukin-6 is a centrally acting endogenous pyrogen in the rat. 177 46

The effects of cyclo-oxygenase inhibitors on interleukin-6 (IL-6) production by human peripheral blood mononuclear cells were examined. Indomethacin and Y-9223, a novel cyclo-oxygenase inhibitor, inhibited the increases in the IL-6 level in the culture medium of both mitogen-stimulated adherent cells and non-adherent cells fractionated from mononuclear cells. Northern blotting showed that the mitogen-induced increase in the expression of IL-6 mRNA was inhibited by indomethacin and Y-9223, indicating that these agents inhibit IL-6 biosynthesis. Aspirin, ibuprofen, and phenylbutazone also inhibited IL-6 production by adherent cells stimulated with lipopolysaccharide (LPS). There was, however, no direct relationship between inhibition of IL-6 and prostaglandin E2 (PGE2) production by these agents. The addition of PGE2 corresponding to the amount produced by adherent cells stimulated with LPS slightly increased IL-6 production by unstimulated adherent cells, but to a lower level than that reached with LPS. An anti-PGE2 antibody partially blocked IL-6 production by adherent cells stimulated with LPS. These results suggest that, in addition to the inhibition of PGE2 production, other mediators including cyclooxygenase products or other action mechanisms are involved in the inhibition of IL-6 production by these drugs.
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PMID:Inhibition by cyclo-oxygenase inhibitors of interleukin-6 production by human peripheral blood mononuclear cells. 181 50

Plasma levels of tumor necrosis factor-alpha (TNF alpha), interleukin-1 (IL-1), and interleukin-6 (IL-6) were monitored after intravenous administration of Escherichia coli endotoxin with or without ibuprofen pretreatment to healthy volunteers. Intravenous endotoxin (n = 7) resulted in elevated plasma TNF alpha concentrations with maximal levels at 90 min (369 +/- 44 pg/ml, P less than .001 vs. saline controls, n = 7). The rise in TNF-alpha was followed by a rise in plasma IL-6 (27 +/- 12.8 ng/ml), peaking 30-90 min thereafter. Pretreatment with ibuprofen (n = 6) caused a significant augmentation and temporal shift in cytokine elaboration with maximal TNF alpha levels (627 +/- 136 pg/ml) at 120 min and IL-6 peaks (113 +/- 66 ng/ml) at 180 min. In ibuprofen-treated volunteers, the additional increase in TNF alpha was paralleled by increased levels of circulating elastase. In vitro experiments suggest a causal relationship between these events. Thus, the cyclooxygenase inhibitor ibuprofen blunts the clinical response to endotoxin but augments circulating cytokine levels and leukocyte degranulation.
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PMID:Pretreatment with ibuprofen augments circulating tumor necrosis factor-alpha, interleukin-6, and elastase during acute endotoxinemia. 198 81

Previous studies have demonstrated considerable prostanoid production by cultured proliferating rat mesangial cells (MC). In this study, human mesangial cells (HMC) were examined during serum-free culture in which the cells were reversibly growth arrested and did not suffer obvious irreversible functional changes. Non-stimulated cells released 2 to 10 pg/24 hr/micrograms cellular protein of PGE2, PGF2 alpha, 6-keto-PGF1 alpha, while TXB2 was not detectable. Stimulation with interleukin-1 beta (IL-1 beta) or tumor necrosis factor alpha (TNF alpha) induced up to 18-fold (IL-1 beta) or up to fourfold (TNF alpha) increases of prostanoid release. Combinations of the two monokines resulted in significant synergistic induction of PGE2 and 6-keto-PGF1 alpha up to 38 times that of control cells. Interleukin-6 (IL-6) and the HMC-mitogen, platelet-derived growth factor-BB (PDGF-BB) only induced marginal increases in HMC prostanoid generation. However, when PDGF-BB or -AB was combined with IL-1 beta or IL-6, prostanoid generation by HMC was synergistically increased up to 222-fold (IL-1 beta) or 12-fold (IL-6) above the control values, with the induction of PGE2 greater than 6-keto-PGF1 alpha greater than PGF2 alpha much greater than TXB2. In the case of IL-1 beta + PDGF-BB the induction of PGE2 release was at least partly due to the synergistic induction of cyclooxygenase activity. These findings demonstrate that both proliferating and reversibly growth arrested HMCs release prostaglandins in response to various inflammatory stimulators and combinations thereof. The findings support the important role of HMC in the regulation of glomerular hemodynamics during inflammatory processes.
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PMID:Monokines and platelet-derived growth factor modulate prostanoid production in growth arrested, human mesangial cells. 210 53

Although its impact on the acute phase response is clear, little is known regarding the regulation of interleukin-6 (hepatocyte-stimulating factor) production. We evaluated its relationship with the potent immunosuppressive eicosanoid PGE2 in endotoxin (LPS)-stimulated Kupffer cells (KC). KC were harvested from collagenase-digested Wistar-Furth rat livers and purified (greater than 95% by phagocytosis) by adherence. Following overnight culture with or without the cyclooxygenase inhibitor indomethacin (10 microM), 5 X 10(5) KC were repleted with fresh media with or without 2.5 micrograms/ml LPS. Supernatant IL-6 levels (ng/ml) were measured with the B9.9 hybridoma proliferative bioassay, and PGE2 levels (ng/ml) by radioimmunoassay. Negligible supernatant IL-6 and PGE2 were measured at all culture intervals in unstimulated KC or those cultured with the LPS-inhibitor polymyxin-B (10 micrograms/ml). With LPS, KC IL-6 production increased in parallel with PGE2 for 24 hr before decreasing as PGE2 continued to rise. When indomethacin treatment blocked KC PGE2 production, IL-6 levels significantly increased. We conclude that PGE2 produced by activated Kupffer cells appears to down-regulate IL-6 secretion. Autocrine effects by PGE2 may locally regulate the hepatic acute phase response by limiting the KC-derived IL-6 available to act on neighboring hepatocytes.
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PMID:Interleukin-6 production by endotoxin-stimulated Kupffer cells is regulated by prostaglandin E2. 236 12


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