UNIPROT:P10145 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10145 (IL-8)
23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present studies, the mechanisms underlying the inhibitory actions of lipocortin-1 on the pyrogenic and thermogenic properties of cytokines were investigated. Central (icv) injection of corticotropin-releasing factor (CRF, 4.7 micrograms) or the recombinant cytokines interleukin (IL)-1 alpha (50 ng), IL-1 beta (5 ng), IL-6 (20 ng), IL-8 (20 ng), or tumor necrosis factor-alpha (TNF-alpha, 1 microgram) in conscious rats produced significant increases in resting oxygen consumption (VO2, 13-26%) and colonic temperature (0.7-1.6 degrees C) within 2 h postinjection. Administration (icv) of a recombinant fragment (NH2-terminus, 1-188 amino acids) of human lipocortin-1 (1.2 micrograms) produced small increases in VO2 (< 5%) and body temperature (< 0.3 degrees C). Pretreatment (-5 min) with lipocortin-1 significantly attenuated the thermogenic and pyrogenic effects of centrally injected IL-1 beta (80% inhibition), IL-6 (60%), IL-8 (80%), or CRF (60%). However, pretreatment with lipocortin-1 failed to modify the actions of IL-1 alpha or TNF-alpha. We have previously demonstrated that the pyrogenic and thermogenic effects of IL-1 beta, IL-6, and IL-8 are dependent on the central actions of CRF, whereas IL-1 alpha and TNF-alpha act independently of CRF. Fever and thermogenesis induced by all of these cytokines (with the exception of IL-8) can also be prevented by administration of a cyclooxygenase inhibitor. The data presented here suggest that the potent antipyretic effects of lipocortin-1 may result from inhibition of the release or actions of CRF rather than modulation of eicosanoid synthesis.
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PMID:Inhibition of central actions of cytokines on fever and thermogenesis by lipocortin-1 involves CRF. 141 82

Our recent studies suggest that lipocortin 1 (LC1), a potential mediator of the anti-inflammatory, antiproliferative and anti-fever actions of glucocorticoids in peripheral tissues, may also contribute to the powerful negative feedback actions of the steroids on the hypothalamo-pituitary-adrenal (HPA) axis. In the present study we have used (1) an in vitro model to examine the influence of a specific neutralizing monoclonal anti-LC1 antibody (anti-LC1 mAb) on the capacity of dexamethasone to suppress the cytokine-induced release of the 41-amino acid corticotropin-releasing factor (CRF-41) and arginine vasopressin (AVP) from the rat hypothalamus and (2) a passive immunization protocol to assess the contribution of LC1 to the inhibitory actions of dexamethasone on the HPA responses to immunological (i.p. injection of interleukin 1 beta, IL-1 beta) and surgical (laparotomy under ether anaesthesia) stress. In vitro, Il-1 alpha (0.2 ng/ml), IL-1 beta (0.5 ng/ml), IL-6 (10 ng/ml) and IL-8 (1 ng/ml) each caused significant increases in the release of immunoreactive (ir)-CRF-41 and ir-AVP from hypothalami removed from rats adrenalectomized 10-12 days before autopsy; these responses were readily inhibited by preincubation of the tissue with dexamethasone (10(-7) M). The inhibitory actions of the steroid were attenuated and, in many instances, abolished by inclusion in the medium of a monoclonal anti-LC1 antibody (LC1 mAb, diluted 1:15,000); an isotype-matched control antibody (antispectrin alpha+beta, diluted 1:15,000) was ineffective in this regard. IL-1 alpha (0.2 ng/ml), IL-1 beta (0.5 ng/ml) and IL-6 (10 ng/ml) also initiated similar increases in the release of CRF-41 and AVP from hypothalami from intact rats which were effectively blocked by dexamethasone (10(-7) M). However, although the inhibitory actions of the steroid on the pharmacologically evoked release of CRF-41 were specifically overcome by anti-LC1 mAb (diluted 1:15,000), the steroid blockade of AVP release was not. In vivo, rats pretreated with either a polyclonal anti-LC1 antibody (anti-LC1 pAb, 1 ml/day s.c. for 2 days) or a corresponding volume of a nonimmune sheep serum (NSS) responded to immunological (IL-1 beta, 3 micrograms/kg i.p.) or surgical (laparotomy under ether anaesthesia) trauma with significant increases in the serum ACTH and corticosterone concentrations. In the NSS-treated groups, dexamethasone (100 micrograms/kg), which had no effect on the prestress concentrations of ACTH and corticosterone in the blood, completely prevented the HPA responses to both IL-1 beta and laparotomy.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Immunoneutralization of lipocortin 1 reverses the acute inhibitory effects of dexamethasone on the hypothalamo-pituitary-adrenocortical responses to cytokines in the rat in vitro and in vivo. 756 34

A total of 105 patients participated in this study, including 10 with chronic glomerulonephritis with normal renal function (CGN patients), 36 uraemic patients (CRF patients), 19 continuous ambulatory peritoneal dialysis patients (CAPD) without peritonitis, three CAPD patients with peritonitis, 37 patients undergoing chronic haemodialysis (HD) divided into short-term HD, 15 patients; medium-term HD, 12 patients; and long-term HD, 10 patients. IL-8 and two other proinflammatory cytokines, IL-6 and TNF alpha were tested using a specific immunoassay. IL-8, IL-6, and TNF alpha serum levels were significantly increased in patients with chronic renal failure compared to their levels in normal individuals (P < 0.0001, P < 0.05 and P < 0.0001 respectively). The most pronounced increment in IL-8, IL-6 and TNF alpha serum levels was observed in CAPD patients (P < 0.0001). CAPD patients without peritonitis showed relatively low levels of IL-8 or IL-6 in peritoneal dialysate effluents (PDE), whereas PDE-TNF alpha were not detectable in almost all patients tested. Patients with peritonitis showed very high serum and PDE levels of IL-8, IL-6 and TNF alpha. The clinical recovery from peritonitis was characterized by a rapid fall in IL-8, IL-6 and TNF alpha in serum and dialysate. HD patients showed a significant increase in serum levels of IL-8 and also IL-6 and TNF alpha compared to normal individuals (P < 0.05, P < 0.05 and P < 0.01 respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interleukin-8 in chronic renal failure and dialysis patients. 781 57

Activation of the immune system is normally associated with widespread alterations in neuroendocrine activity, the profile of which depends upon the species and on the severity and duration of the stimulus. Particularly important in this regard is the activation of the hypothalamo-pituitary-adrenocortical (HPA) axis for the consequent rise in circulating glucocorticoids serves to contain the ensuing pathophysiological responses and thus to restore homeostasis. In the present study, in vivo and in vitro techniques have been used to examine the influence of various immunokines on the HPA axis and to determine whether their actions are modulated by glucocorticoids and lipocortin 1 (LC1). In vivo interleukin-1 beta (IL-1 beta), given orally or peripherally, produced increases (P < 0.01) the serum corticosterone concentration which were reversed by pretreatment with dexamethasone. IL-1 beta also produced glucocorticoid reversible increases in the release of the two corticotrophin releasing factors, CRF-41 and AVP, from the hypothalamus in vitro (P < 0.01) as also did IL-1 alpha, IL-6 and IL-8. By contrast, none of these cytokines influenced directly the release of ACTH from pituitary tissue in vitro. The inhibitory actions of the glucocorticoids on the HPA responses to cytokines observed in vivo and in vitro were mimicked by LC1 and reversed by neutralizing anti-LC1 antisera. Our results demonstrate a role of cytokines, glucocorticoids and LC1 in effecting the interplay between the brain-neuroendocrine and immune system which may be critical to host defence in conditions of both health and disease.
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PMID:Cytokines, glucocorticoids and neuroendocrine function. 783 Nov 93

Growing evidence suggests that cytokine expression is influenced by locally produced mediators, thus modifying the pluripotential effects of cytokines toward a tissue-specific inflammatory reaction. The granulocyte inhibitory protein (GIP), a 23-kDa protein found to be significantly overexpressed in patients with chronic renal failure, increases autocrine transcription and expression of interleukin (IL) 6 and IL-8 in human mesangial cells. Moreover, GIP alone induced the transcription of c-jun mRNA; however, in combination with IL-6, it stimulated de novo synthesis of DNA and the transcription of both c-jun and c-fos genes. The data suggest that the overall effect of GIP results in the modulation of the glomerular response to injury and contributes to the progression of glomerulosclerosis.
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PMID:A granulocyte inhibitory protein overexpressed in chronic renal disease regulates expression of interleukin 6 and interleukin 8. 827 82

Our recent studies indicate that lipocortin 1 (LC1), a putative second messenger protein for the anti-inflammatory steroids in peripheral tissues, may also contribute to the regulatory actions of the glucocorticoids on the hypothalamo-pituitary-adrenal axis. In the present study we have used in vitro and in vivo models to compare the effects of adrenalectomy, LC1 and dexamethasone on the cytokine-induced secretion of the 41-amino acid corticotrophin releasing factor (CRF-41) and arginine vasopressin (AVP) by the rat hypothalamus. In addition, western blot analysis was used to examine the influence of dexamethasone on the expression of LC1 in the hypothalamus. In vitro, interleukins- (IL-) 1 alpha (100 and 200 pg/ml), 1 beta (0.5 and 1.0 ng/ml) and 8 (0.25-1.0 ng/ml) readily initiated the release of CRF-41 and AVP from hypothalami removed from intact rats. IL-6 (10 and 20 ng/ml) was also an effective CRF-41 secretagogue but, unlike the other interleukins tested, it was ineffective with regard to AVP. Adrenalectomy 7-14 days prior to autopsy increased significantly (p < 0.01) the magnitude of the CRF-41 responses to IL-1 alpha, IL-1 beta and IL-6 but not to IL-8. In contrast however, while hypothalamic tissue from adrenalectomized rats, unlike that from intact animals, responded to IL-6 (5-20 ng/ml) with a pronounced hypersecretion of AVP, the AVP responses to IL-1 alpha and IL-1 beta were largely unaffected by adrenalectomy as too were those to IL-8. The marked increases in CRF-41 and AVP release from hypothalami from adrenalectomized rats initiated in vitro by IL1 alpha, IL-1 beta, IL-6 and IL-8 were readily overcome by preincubation of the tissue with dexamethasone (10(-7) M). In addition, the steroid caused 'externalization' of two species of immunoreactive (ir-) LC1 (37 and 58 kDa) by the hypothalamic cells but failed to influence the total LC1 content of the tissue. The inhibitory effects of dexamethasone on the cytokine-induced release of CRF-41 in vitro were mimicked by LC1 (10 ng/ml) which alone had no effect on the basal release of the peptide. However, unlike dexamethasone, LC1 failed to influence the concomitant release of AVP from the hypothalamic tissue elicited by IL1 alpha, IL-1 beta or IL-8 and potentiated that evoked by IL-6.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Modulation of the hypothalamo-pituitary-adrenocortical responses to cytokines in the rat by lipocortin 1 and glucocorticoids: a role for lipocortin 1 in the feedback inhibition of CRF-41 release? 841 17

The results of the present study, summarized in Table 2, demonstrate that different species and strains of rodents (rats and mice) and birds (chickens) exhibit rather specific fever response. Systemic administration of LPS caused monophasic elevation in Tb of chickens, biphasic changes in Tb of rats (initial drop followed by an increase in Tb), whereas mice failed to develop hyperthermia and responded by a decreased Tb. The LPS-induced alterations in hypothalamic prostanoid synthesis were also rather species-specific and differ markedly even between the two strains of mice. We failed to find a common direct correlation between LPS-induced changes in Tb and hypothalamic prostanoid production in rodents (rats and mice). This observation is supported by our recent study on age-related changes in fever response in rats, where we found that hypothalami of LPS-treated old and young adult rats produced similar amounts of PGE2 and PGI2, in spite of more pronounced and prolonged hypothermia, and a delayed elevation in Tb of old rats, as compared with young (Fraifeld et al., 1995b). Moreover, the hypothalamus of febrile chickens did not display any detectable activation of PGE2 production, suggesting that PGE2 is not a common central mediator of fever in homeotherms (Fraifeld et al., 1995a). Apparently, the actual body temperature not always reflects the functional state of central thermostat, and increased PGE2 production in hypothalamus would not directly, at least in rodents, lead to body temperature elevation. Furthermore, peripheral effects, including PG-mediated ones, of pyrogens can interfere and even overcome their centrally-mediated effects (Morimoto et al., 1991; Burysek et al., 1993). Previously, we have shown that no additional elevation in hypothalamic PGE2 production occurs in response to doses of LPS over 10 micrograms in rats and 25 micrograms in mice, while the increased doses led to further changes in Tb response (Kaplanski et al., 1993). Morimoto et al. (1991) have considered that PGE2 acts centrally to cause fever and peripherally to cause hypothermia, and, hence, these opposing actions, both being induced by LPS, may act together to determine the final thermoregulatory response. Other possibilities could be related to counterbalance of endogenous antipyretics (Kluger, 1991; Kozak et al., 1995), that may occur not only at the level of thermoregulatory center but also outside the CNS (Klir et al., 1995), and to the existence of PG-independent mechanisms of LPS fever. The latter have been shown for IL-8 (Rothwell et al., 1990; Zampronio et al., 1994) and MIP-1 (Davatelis et al., 1989; Minano et al., 1990; Hayashi et al., 1995; Lopez-Valpuesta and Myers, 1995), which are, apparently, mediated via CRF (Strijbos et al., 1992; Zampronio et al., 1994), and INF-alpha, mediated via the opioid receptor mechanisms (Hori et al., 1991, 1992). However, it has been shown recently that in different species the same pyrogenic cytokines (IL-8) may induced fever via different, PG-independent (in rats; Zampronio et al., 1994) or PG-dependent (in rabbits; Zampronio et al., 1995) mechanisms. It should be noted that fever response is not always accompanied by an elevation in Tb. The final effect of pyrogens on body temperature depends upon the balance between heat production and heat loss, which in turn is highly dependent upon body size and ambient temperature, especially in small animals. Perhaps, the hypothermic response observed in our mice and rats at 22 degrees C may be in part attributed to ambient temperature, which was below a thermoneutral zone. The reduced febrile response is considered, at least in part, to contribute to an increased mortality and prolonged recovery from infections (Kluger, 1986). From this point, it is difficult to suggest whether the hypothermia observed in our mice and rats could be of somewhat adaptive significance. It has been shown that at the ambient temperature of 30 degrees C, Swiss Webster mice can re
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PMID:Brain eicosanoids and LPS fever: species and age differences. 963 34

In many diseases and acute inflammatory disorders, important components of pathological processes are linked to the neutrophils' ability to release a complex assortment of agents that can destroy normal cells and dissolve connective tissue. This review summarizes the mechanisms of tissue destruction by neutrophils and the role of kidney-specific factors that promote this effect. Nicotinamide adenine dinucleotide phosphate H (NADPH) oxidase is a membrane-associated enzyme that generates a family of reactive oxygen intermediates (ROI). There is increasing evidence that ROIs are implicated in glomerular pathophysiology: ROIs contribute to the development of proteinuria, alter glomerular filtration rate, and induce morphological changes in glomerular cells. Specific neutrophil granules contain microbicidal peptides, proteins, and proteolytic enzymes, which mediate the dissolution of extracellular matrix, harm cell structures or cell function, and induce acute and potentially irreparable damage. Although both ROI and neutrophil-derived proteases alone have the potential for tissue destruction, it is their synergism that circumvents the intrinsic barriers designed to protect the host. Even small amounts of ROI can generate hypochlorus acid (HOCl) in the presence of neutrophil-derived myeloperoxidase (MPO) and initiate the deactivation of antiproteases and activation of latent proteases, which lead to tissue damage if not properly controlled. In addition, neutrophil-derived phospholipase products such as leukotrienes and platelet-activating factor contribute to vascular changes in acute inflammation and amplify tissue damage. Increasing evidence suggests that mesangial cells and neutrophils release chemotactic substances (eg, interleukin 8), which further promote neutrophil migration to the kidney, activate neutrophils, and increase glomerular injury. Also, the expression of adhesion molecules (eg, intercellular adhesion molecule 1 on kidney-specific cells and beta-2-integrins on leukocytes) has been correlated with the degree of injury in various forms of glomerulonephritis or after ischemia and reperfusion. Together, these results suggest that neutrophils and adhesion molecules play an important role in mediating tissue injury with subsequent renal failure. Conversely, chronic renal failure reduces neutrophil function and thereby can increase susceptibility to infection and sepsis.
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PMID:Neutrophils and renal failure. 1043 Sep 93

Chronic renal failure (CRF) courses with both systemic inflammatory reaction and haemostatic activation. We explored the relationship of these processes with plasma levels of free, activated protein C (APC) and complexes of APC with its inhibitors in patients with CRF under conservative treatment. Plasma concentrations of inflammatory cytokines [tumour necrosis factor alpha (TNFalpha) and interleukin 8], acute-phase proteins (C-reactive protein, fibrinogen, alpha1-anti-trypsin and von Willebrand factor), and markers of haemostatic activation (thrombin-anti-thrombin complexes, plasmin-anti-plasmin complexes, and fibrin and fibrinogen degradation products) were higher in patients than in controls. Inflammatory and haemostatic markers were significantly and positively correlated. Total plasma APC and APC:alpha1-anti-trypsin (alpha1AT) complexes were 44% and 75% higher in patients than in controls (P = 0.0001), whereas free APC was 20% lower (P < 0.015). No significant difference was observed in APC:protein C inhibitor (PCI) complexes between both groups. The free/total APC ratio was significantly lower in patients than in controls (P < 0.0001). Total plasma APC and APC:alpha1AT were positively correlated with activation markers of haemostasis and acute-phase proteins, whereas free APC was inversely correlated with plasma levels of creatinine, acute-phase proteins and fibrin degradation products (FnDP). Systemic inflammation and activation of haemostasis are interrelated processes in CRF. APC generation was increased in response to elevated thrombin production, but the inflammatory reaction, associated with increased synthesis of alpha1AT, reduced its anticoagulant effect. Lower free plasma APC in CRF may be pathogenically associated with atherothrombosis, a major cause of death in this disease.
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PMID:Increased activation of protein C, but lower plasma levels of free, activated protein C in uraemic patients: relationship with systemic inflammation and haemostatic activation. 1144 82

Astrocytes play key roles in CNS development, inflammation, and repair by producing a wide variety of cytokines, chemokines, and growth factors. Understanding the regulation of this network is important for a full understanding of astrocyte functioning. In this study, expression levels of 268 genes encoding cytokines, chemokines, growth factors, and their receptors were established in cultured human adult astrocytes using cDNA arrays. Also, changes in this gene profile were determined following stimulation with TNFalpha, IL-1beta, and IFNgamma. The data obtained reveal a highly reproducible pattern of gene expression not only between different astrocyte cultures from a single source, but also between astrocytes from different donors. They also identify several gene products not previously described for human astrocytes, including a.o. IL-17, CD70, CD147, and BIGH3. When stimulated with TNFalpha astrocytes respond with increased expression of several genes, notably including those encoding the chemokines CCL2 (MCP-1), CCL5 (RANTES), and CXCL8 (IL-8), growth factors including BMP-2A, BMP-3, neuromodulin (GAP43), BDNF, and G-CSF, and receptors such as the CRF receptor, the calcitonin receptor (CTR), and TKT. The response to IL-1beta involves largely the same range of genes, but responses were blunted in comparison to the TNFalpha response. Treatment with IFNgamma had no or only marginal effects on expression of any of the 268 genes analyzed. Astrocytes treated with a mixture of all three stimuli together displayed responses that are largely similar to those found in response to TNFalpha or IL-1beta alone, with only few additional synergistic effects.
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PMID:Cytokine, chemokine and growth factor gene profiling of cultured human astrocytes after exposure to proinflammatory stimuli. 1289 3

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