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

The neuropeptide alpha-melanocyte stimulating hormone [alpha-MSH(1-13)] occurs in the pituitary, brain, skin and other tissues and receptors for this molecule are likewise widespread. In previous research, this tridecapeptide, which shares its amino acid sequence with ACTH(1-13), was shown to have both potent antipyretic activity and a role in the endogenous control of the febrile response. alpha-MSH(1-13) and its COOH-terminal tripeptide were subsequently found to inhibit inflammation induced by general stimuli such as topical application of an irritant. The aim in the present experiments was to determine if these peptides can inhibit acute inflammatory responses induced in mice by injection of individual cytokines, endogenous pyrogen (EP), a natural cytokine mixture, and other mediators of inflammation. Inflammation induced in the mouse ear by rIL-1 beta, rIL-6 or rTNF-alpha was inhibited by alpha-MSH and a D-valine-substituted analog of alpha-MSH(11-13) whereas substantial doses of alpha-MSH(1-13) did not alter inflammation induced by LTB4, PAF and IL-8. Both peptides inhibited edema caused in the mouse paw by local injection of EP. The results indicate that alpha-MSH molecules antagonize the actions of certain cytokine mediators of inflammation, consistent with previous observations of anti-cytokine activity of these peptides. Failure to inhibit edema caused by LTB4, PAF and IL-8 suggests that, in inflammation induced by general stimuli, such as EP, the peptides act prior to the release of these mediators of the inflammatory response. Because of the anticytokine/anti-inflammatory actions of the alpha-MSH molecules they may be useful in understanding the cytokine network and for treatment of inflammatory diseases.
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PMID:Alpha-MSH peptides inhibit acute inflammation induced in mice by rIL-1 beta, rIL-6, rTNF-alpha and endogenous pyrogen but not that caused by LTB4, PAF and rIL-8. 132 96

It has previously been shown that interleukin-1 (IL-1) directly stimulates the release of CRH-41 from rat hypothalamus in vitro, suggesting that cytokines may mediate the effects of changes in immune state on the hypothalamo-pituitary adrenal axis (HPA). However, it is likely that several cytokines can cause changes in neuroendocrine function, and we have now investigated a series of others for central activity on the HPA: IL-2, IL-6, IL-8, tumor necrosis factor (cachectin), interferon-alpha 2, and interferon-gamma. The static rat hypothalamic incubation system used involves fresh hypothalamic explants with consecutive 20-min incubation, and estimation of CRH-41 concentrations in the medium by a specific RIA; the acute effects of cytokines on ACTH release from rat dispersed pituitary cells were also measured. IL-6 increased hypothalamic CRH-41 secretion in the range 10-100 U/ml, but had no effect on isolated median eminences incubated in vitro under the same conditions. IL-6 (1-1000 U/ml) also had no effect on the secretion of ACTH from freshly dispersed rat anterior pituitary cells when administered in 10-min pulses. The effects of both IL-1 and IL-6 were antagonized by blockade of the eicosanoid cyclooxygenase pathway, but not by lipooxygenase blockade. Neither IL-2 (1-10000 U/ml), IL-8 (0.1-10 nM), tumor necrosis factor (10-1000 U/ml), interferon-alpha 2 (10-1000 U/ml) nor interferon-gamma (10-1000 U/ml) had any effect on hypothalamic CRH-41 release or pituitary ACTH release. It is therefore concluded that IL-6, like IL-1, can exert a potent enhancing effect on the HPA by acutely stimulating the secretion of CRH-41 from the hypothalamus at a site above the level of the median eminence, at concentrations known to occur in human plasma and cerebrospinal fluid. These effects are probably mediated by cyclooxygenase products. Acute stimulatory effects of the other cytokines investigated on the HPA are unlikely to be exerted through changes in either CRH-41 or ACTH directly.
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PMID:Interleukins-1 and -6 stimulate the release of corticotropin-releasing hormone-41 from rat hypothalamus in vitro via the eicosanoid cyclooxygenase pathway. 184 5

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

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

The inflammatory mechanisms which take place in microcrystalline arthropathies can be divided into several stages, each of them being characterized by the activation of a set of mediators. The process begins with activation by crystals of resident cells in the synovial fluid which release various pro-inflammatory factors including several cytokines. Among these, interleukin 1 (IL-1) and tumor-necrosis factor alpha (TNF-alpha) have multiple effects and play a predominant role in the starting of inflammation. With the contribution of humoral factors, also activated by the crystals, IL-1 and TNF-alpha activate notably the endothelial cells to allow leucocyte extravasation. The attraction and massive activation of polymorphonuclear neutrophils (PMNs) which then occurs and characterizes acute microcrystalline arthropathies mainly depend on IL-8, another cytokine secreted by synoviocytes. At the same time, an acute phase systemic reaction principally induced by IL-6 develops. When inflammation is prolonged mechanisms of tissue destruction begin to act, notably by releasing proteases induced by IL-1 and TNF-alpha. These mechanisms are counterbalanced by release of antiproteases, notably those induced by the transforming growth factor beta (TGF-beta) and by IL-6. Finally, these inflammatory processes may limit themselves or even stop spontaneously, due to a series of control mechanisms including cytokines with anti-inflammatory effects, ACTH release and physico-chemical changes in crystals.
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PMID:[Mechanisms of microcrystalline inflammation]. 817 68

Interleukin-6 (IL-6) is a proinflammatory cytokine that has been shown to mediate, in addition to immune reactions, various endocrine and central nervous components of the acute phase response. In this context, the present study aimed to specify the contributions of IL-6 to the regulation of pituitary-adrenal secretory activity and GH and TSH secretion, as well as to the regulation of central nervous sleep and mood in healthy men. Effects of a low dose of IL-6 (0.5 microgram/kg body weight) were assessed, inducing plasma IL-6 concentrations closely comparable with those typically observed after infectious challenge. Each of the 16 male subjects participated in two 14-h sessions (between 1800 and 0800 h), receiving either placebo or human recombinant IL-6 sc at 1900 h. Blood was collected repeatedly to determine plasma hormone levels, serum concentrations of cytokines, and C-reactive protein. Moreover, mood was assessed, and sleep recordings were obtained between 2300 and 0700 h. The cytokine induced a prolonged increased in plasma concentrations of ACTH and cortisol (P < 0.001), but led to a decrease in TSH concentrations (P < 0.01). In response to IL-6, subjects reported fatigue and felt more inactive and less capable of concentrating than after placebo. Sleep architecture was altered significantly by the cytokine. Slow-wave sleep was decreased during the first half and increased during the second half of sleep. Rapid eye movement sleep during the entire nocturnal sleep time was significantly decreased. After IL-6, body temperature rose slightly. C-reactive protein concentrations were dramatically increased 12.5 h after substance administration (P < 0.001). IL-6 did not affect serum concentrations of IL-2, IL-8, interferon-alpha, and interferon-gamma. The results underscore the importance of IL-6 in the cascade of cytokines for the neuroendocrine response during the acute phase reaction. In addition, IL-6 appears to be involved in changes of sleep and behavior accompanying infection and inflammatory disorders.
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PMID:Acute effects of recombinant human interleukin-6 on endocrine and central nervous sleep functions in healthy men. 958 58

Ovalbumin (OvA) inhalation by sensitized guinea-pigs caused a pronounced rise in interleukin (IL)-5 in bronchoalveolar lavage (BAL) fluid at both 3 and 24 h after antigen exposure. The increased levels at 24 h were attenuated by the phosphodiesterase inhibitors Ro 20-1724 and aminophylline and by dexamethasone, all of which also attenuated the concurrent lung eosinophilia. The rise in IL-5 at 3 h was additionally attenuated by the PDE3 inhibitor, siguazodan, which failed to attenuate the eosinophilia at 24 h. These results suggest a pivotal action of these compounds on the later rise in IL-5. Ro 20-1724, aminophylline, siguazodan and dexamethasone attenuated a rise in IL-8 levels in BAL fluid at 3 h and the subsequent neutrophilia at 24 h. There was no increase in plasma ACTH at 3 and 24 h after OvA challenge but cortisol levels were elevated at 3 h. This was inhibited by Ro 20-1724, siguazodan and dexamethasone. Thus, elevation of plasma cortisol does not explain the anti-inflammatory actions of these compounds. Aminophylline, however, did raise plasma cortisol at both 3 and 24 h after antigen challenge which may be an important further mechanism of action for this compound.
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PMID:The potential roles of cytokines, IL-5 and IL-8, and plasma cortisol in the anti-inflammatory actions of phosphodiesterase inhibitors in sensitized guinea-pig airways. 977 91

Human dermal microvascular endothelial cells (HDMEC) are capable of mediating leukocyte-endothelial interactions by the expression of cellular adhesion molecules and the release of proinflammatory cytokines and chemokines during cutaneous inflammation. Recent studies support the important role for proopiomelanocortin (POMC) peptides, such as alpha-melanocyte stimulating hormone (alpha-MSH), as immunomodulators in the cutaneous immune system. The purpose of the studies described here was to determine whether HDMEC serves as both target and source for POMC peptides. RT-PCR and Northern blot studies demonstrated the constitutive expression of mRNA for the adrenocorticotropin (ACTH) and alpha-MSH-specific melanocortin receptor 1 (MC-1R) in HDMEC, and the microvascular endothelial cell line HMEC-1 that could be upregulated by stimulation with IL-1 beta and alpha-MSH. HDMEC responded to stimulation by alpha-MSH with a dose- and time-dependent synthesis and release of the CXC chemokines, IL-8 and GRO alpha. Likewise, alpha-MSH augmented HDMEC chemokine release induced by TNF or IL-1. HD-MEC were found to constitutively express POMC and prohormone convertase 1 (PC-1); the latter being required to generate ACTH from the POMC prohormone. POMC and PC-1 mRNA expression are increased as a result of stimulation with UVB and UVA1 radiation, IL-1, and alpha-MSH. In addition, UV-radiation is capable of inducing the release of HDMEC, ACTH, and alpha-MSH in a time- and dose-dependent fashion. Thus, these data provide evidence that HDMEC are capable of expressing functional MC-1R, POMC, and PC-1 mRNA; and of releasing POMC peptides with UV light, IL-1, and alpha-MSH as regulatory factors. The expression and regulation of these peptides may be of importance, not only for the autocrine or paracrine regulation of physiologic functions of dermal endothelial cells, but also for the regulation of certain microvascular-mediated cutaneous or systemic inflammatory responses.
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PMID:Expression of functional melanocortin receptors and proopiomelanocortin peptides by human dermal microvascular endothelial cells. 1081 57

An activation of the immune system might contribute to the therapeutic effect of whole body hyperthermia (WBH) in cancer patients. We explored immune and endocrine responses in patients undergoing high-temperature WBH. Identical parameters were investigated in a separate group of healthy volunteers undergoing physical exercise to rule out effects of sympathetic activation. Lymphocyte subpopulations, lymphocytic expression of a range of adhesion molecules, and serum concentrations of a variety of hormones and cytokines were assessed in cancer patients undergoing high-temperature (60 min at 41.0-41.8 degrees C) WBH (n = 25) and in a separate group of healthy volunteers (n = 10) performing strenuous physical exercise. WBH induced an increase in human growth hormone (hGH), ACTH, and cortisol as well as in TNF-alpha, IL-6, IL-8, and IL-12R. We observed an increase in natural killer (NK) cells and CD56+ NK T cells shortly after initiation of WBH. In contrast, we found a decrease in T cells expressing L-selectin (CD62L) or alpha4beta7 integrin adhesion molecules mediating homing to lymphatic tissues. Accordingly, we observed a decrease in CD45RA+CCR7+ naive and CD45RA-CCR7+ central memory T cells. Numbers of CD45RA-CCR7- memory effector and CD45RA+CCR7 terminally differentiated T cells, on the other hand, remained unchanged. No comparable changes were observed in the group of healthy volunteers. In conclusion, patients with solid tumors treated with WBH show an increase in NK and NK T cells. In a later phase, plasma concentrations of IL-8, hGH, and cortisol increase, correlated with an influx of neutrophils into the peripheral blood. The alterations in T-cell populations suggest that WBH may induce naive and central-memory T cells to enter lymphatic tissue to await antigen exposure and effector T cells to migrate into peripheral tissues to exert their effector function. Although the exercise group may not be an appropriate control to proof the effect of WBH, these changes were not seen in the healthy volunteers performing physical exercise.
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PMID:Patients with solid tumors treated with high-temperature whole body hyperthermia show a redistribution of naive/memory T-cell subtypes. 1625 30

Depression is a multicausal disorder and has been associated with the risk to develop cancer, dementia, diabetes, epilepsy and stroke. As a metabolic disorder depression has been associated with obesity, diabetes, insulin sensitivity, neuropeptide Y, glucose regulation, poor glycemic control, glucagone-like peptide-1, cholezystokinin, ghrelin, leptin, the endocannabinoid system, insulin-like growth factor and gastrin-releasing peptide. As a cardiovascular disease a close relationship exists between depression and blood pressure, heart rate, norepinephrine, sympathetic tone, vascular resistance, blood viscosity, plasma volume, intima thickness and atherosclerosis. Additionally blood coagulation, fibrinolysis, D-dimers, plasminogen activator inhibitor-1 protein, platelet activation, VEGF, plasma nitric oxide and its synthase are changed in depressed patients. As an endocrinological and stress disorder depression has been connected with the concentration of free T4, TSH, CRH, arginine vasopressin, corticotrophin, corticosteroid release and ACTH. Depression as an inflammatory disorder is mediated by pro-inflammatory cytokines, interleukin-1, interleukin-6, TNF-alpha, soluble interleukin-2 receptors, interferon-alpha, interleukin 8, interleukin-10, hs-CRP, acute phase proteins, haptoglobin, toll like receptor 4, interleukin-1beta, mammalian target of rapamycin pathway, substance P, cyclooxygenase-2, prostaglandin-E2, lipid peroxidation levels and acid sphingomyelinase. Nutritional factors might influence depression risk, i.e. the consumption of folate, omega-3 fatty acids, monounsaturated fatty acids, olive oil, fish, fruits, vegetables, nuts, legumes, vitamin B6 and vitamin B12. The neurodegenerative hypothesis of depression explains decreased hippocampal volumes in depressed patients and changes of neurotrophic support by BDNF, erythropoietin, GDNF, FGF-2, NT3, NGF and growth hormone. In this context, a fast neuroprotective and antidepressant effect has also been observed by ketamine, which acts via the glutamatergic system. Hence, GABA, AMPA, EAAT, NMDA- and metabotropic glutamate receptors (mGluR1 to mGluR8) have gained interest in depression recently. Alternative, causative or also easy available treatment strategies beyond serotonin and noradrenaline reuptake inhibition might be a major topic of future psychiatric care. In this review, an attempt is made to overview concepts of the disease and search for perspectives on antidepressant treatment strategies beyond approved medications.
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PMID:Molecular mechanisms of depression: perspectives on new treatment strategies. 2373 22


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