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)

Whereas the stimulatory effect of interleukin-6 (IL-6) on the hypothalamic-pituitary-adrenal (HPA) axis is well established, its mode of action in this axis has yet to be fully elucidated. To further study the role of IL-6 in the HPA axis, we compared the expression of IL-6 messenger RNA (mRNA) in the rat hypothalamus, pituitary, and adrenal gland with that in the spleen after ip or intracerebroventricular (icv) administration of bacterial lipopolysaccharide (LPS). After either ip or icv administration, LPS induced the expression of IL-6 mRNA, which consists of 1.2 kilobases (kb) and 2.4 kb subclasses, in all these tissues of the HPA axis as well as in the spleen. Although we used 100 times less amount of LPS for the icv administration than that used for ip LPS, plasma ACTH levels in both the conditions rapidly reached comparable levels. This icv dose induced IL-6 mRNA expression in the hypothalamus faster than ip dose but also stimulated IL-6 mRNA expression in the hypothalamus, pituitary, and adrenal gland more effectively and smoothly than the ip LPS dose did. Northern blot analysis revealed that in the hypothalamus, pituitary, and adrenals, the predominant subclass of IL-6 mRNA was not 1.2 kb but 2.4 kb. In contrast, this subclass was the minor component in the spleen induced under the same circumstances. These findings indicate that IL-6-synthesizing cells in the HPA axis differ in character from those in the spleen, and that LPS applied in vivo may modulate IL-6 expression in these cells directly and/or indirectly through secondarily activated functions in the neuronal or endocrine systems.
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PMID:Bacterial lipopolysaccharide-induced expression of interleukin-6 messenger ribonucleic acid in the rat hypothalamus, pituitary, adrenal gland, and spleen. 824 80

Fever is induced by interactions of bacterial pyrogens with cells from the immune system, which subsequently release a cascade of cytokines. After intramuscular injection of lipopolysaccharide (LPS) from E. coli, increased amounts of tumor necrosis factor (TNF) and interleukin-6 (IL-6) can be measured in blood plasma and in perfusates of the anterior hypothalamus, where body temperature is regulated. These substances are therefore candidates to be involved in the modification of thermoregulatory structures leading to the febrile rise in body temperature. This increase of body temperature is limited and sometimes even prevented by the actions of endogenous antipyretic neuropeptides like arginine vasopressin (AVP), adrenocorticotropin (ACTH) and melanocyte-stimulating hormones (MSHs) liberated within the brain or systemically during fever. For AVP, most experimental evidence confirms antipyretic pathways from the hypothalamic paraventricular nucleus to the septal area of the limbic system, which are activated during fever and by several stressful stimuli. Fever and endogenous antipyresis are interconnected and result from interactions between the immune system and the central nervous system.
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PMID:Neurobiological concepts of fever generation and suppression. 825 4

The present study compares the effects of endotoxin, a key factor in gram-negative bacterial infection, and of corticotropin-releasing hormone (CRH) on ACTH and cortisol secretion in healthy male volunteers in a placebo-controlled design. Endotoxin (isolated from Salmonella abortus equi; 0.4 ng/kg body weight) induced a significantly delayed and prolonged increase of ACTH and cortisol secretion as compared to CRH (100 micrograms), supporting the hypothesis that different intermediate mechanisms are involved (baseline/peak: ACTHEndotoxin vs. ACTHCRH: 140 +/- 40 min vs. 44 +/- 17 min (p < 0.001); CortisolEndotoxin vs. CortisolCRH: 113 +/- 51 min vs. 66 +/- 31 min (p < 0.05); peak/baseline: ACTHEndotoxin vs. ACTHCRH: 244 +/- 79 min vs. 200 +/- 25 min (p < 0.05); CortisolEndotoxin vs. CortisolCRH: 278 +/- 76 min vs. 182 +/- 16 min (p < 0.001)). Activation of the hypothalamo-pituitary-adrenocortical (HPA) system by endotoxin in men is associated with increased interleukin-6 (peak value: 124 +/- 109 pg/ml) and tumor necrosis factor-alpha (peak value: 69 +/- 53 pg/ml) plasma levels which, probably together with locally produced interleukin-1, stimulate the HPA system both at the hypothalamic and (to a lesser degree) at the pituitary site. Provided that strictly controlled laboratory conditions are applied, the endotoxin challenge test presented here may serve as an appropriate and safe tool to explore an individual's capacity for neuroendocrine adaptation to a bacterial stressor, thus providing information complementary to the CRH test.
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PMID:Endotoxin- and corticotropin-releasing hormone-induced release of ACTH and cortisol. A comparative study in men. 826 45

We have previously shown that bioactive interleukin-6 (IL-6) is produced by rat and mouse (anterior) pituitary cells in vitro. Since the amount produced correlated with the presence of S-100-containing folliculostellate (FS) cells, these cells were suggested to be a source of IL-6 in the anterior pituitary (AP) lobe. In the present study we used immunocytochemical techniques to confirm this presumption. Freshly isolated mouse pituitary cells were subjected to immunocytochemical procedures whereby two different (neutralizing) monoclonal antibodies (MAb) against mouse IL-6 (6B4 and 20F3) and a polyclonal antiserum raised against bovine S-100 were used as primary antibodies. Single immunostaining revealed a small portion of mouse pituitary cells (about 6.5%) to be positive for IL-6 immunoreactivity with both antibodies. Importantly, the same proportion of cells was found to be IL-6 positive if only the AP was used as the cell source. About 7.5% of the pituitary cells stained for the presence of S-100 immunoreactivity. Positive staining for IL-6 was also found in pituitary cell samples from 2-day-old monolayer cultures and from redispersed 9-day-old histotypic aggregates, which both secreted bioassayable IL-6. In contrast, no IL-6 staining was found in AtT-20 cells, an established ACTH-secreting tumor cell line of the mouse pituitary which did not secrete bioactive IL-6. The specificity of the IL-6 immunostaining was demonstrated by a total loss of staining when MAb 6B4 was omitted or replaced by irrelevant rat IgG. Conclusively, pre-adsorption of the anti-IL-6 MAb (6B4) with recombinant mouse IL-6 totally abolished staining of pituitary cells. Double immunostaining for IL-6 and S-100 revealed that most if not all of the IL-6-containing pituitary cells were positive for S-100. Few of the S-100-containing cells did not stain for IL-6. These results confirm our previous hypothesis that FS cells, characterized by immunostaining of S-100 protein, contain bioactive and immunoreactive IL-6 and therefore are very likely producers of IL-6 in the AP. Furthermore, our results suggest that IL-6 is implicated in the local regulatory role ascribed to FS cells in the pituitary gland.
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PMID:Immunocytochemical evidence that S-100-positive cells of the mouse anterior pituitary contain interleukin-6 immunoreactivity. 841 56

Although plasma corticosteroid concentrations can be measured accurately, the biological effect on the target tissue is uncertain. The availability of an accurate measure of corticosteroid sensitivity would potentially clarify the putative roles of endogenous glucocorticoids in illnesses such as inflammatory disease and obesity and allow evaluation of an additional regulatory level of glucocorticoid action. To measure corticosteroid sensitivity, we developed an assay based on the inhibition by dexamethasone (Dex) of lipopolysaccharide (LPS)-induced Interleukin-6 (IL-6) production and release in whole unseparated blood in vitro. LPS induced a dose-dependent increase in IL-6 concentrations up to 34 +/- 6.6 ng/mL, reaching plateau levels after 8 h, whereas Dex dose dependently inhibited LPS-induced IL-6 production. Involvement of the glucocorticoid receptor in this response was supported by abrogation of Dex (10(-7) mol/L) inhibition of IL-6 production by the glucocorticoid receptor antagonist RU 38486. To determine whether corticosteroid sensitivity is a dynamic phenomenon, we subjected healthy males to a graded quantifiable exercise associated with increases in plasma ACTH and cortisol. Before exercise, 3 x 10(-8) mol/L Dex inhibited LPS-induced IL-6 production in vitro; after exercise, 3 x 10(-8) and 10(-7) mol/L Dex were unable to inhibit IL-6 production. We conclude that Dex suppression of LPS-induced IL-6 production is an effective means of determining corticosteroid sensitivity, and that corticosteroid sensitivity in human subjects is a dynamic, rather than a static, phenomenon.
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PMID:Changes in corticosteroid sensitivity of peripheral blood lymphocytes after strenuous exercise in humans. 855 Jul 57

Systemic administration of human interferon-alpha stimulates the pituitary-adrenal axis in men, but the exact mechanism still remains to be established. The present study was undertaken to examine the hypothesis that interferon-alpha may alter the circulating concentrations of the cytokines which involve the activation of the pituitary-adrenal axis. Eleven patients with chronically active hepatitis C were treated with human lymphoblastoid interferon-alpha (IFN: 6 x 10(6) IU/day) and changes in plasma adrenocorticotropin (ACTH), serum cortisol and cytokine concentrations were observed on both the first and second days of the treatment. Subcutaneous administration of IFN significantly increased plasma ACTH and serum cortisol concentrations by 3 h after the injection. Serum interleukin-6 (IL-6) increased with the increase in circulating ACTH and cortisol. There was a significant correlation between serum cortisol and IL-6 concentrations at 3 h. In contrast, an increase in serum interleukin-1 beta was only observed in one case. On the second day of IFN treatment, simultaneous administration of 25 mg diclofenac sodium eliminated the IFN effects on circulating ACTH, cortisol and IL-6 concentrations. The present studies demonstrated that circulating IL-6 increases after systemic IFN administration, resulting in activation of the pituitary-adrenal axis.
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PMID:Increase in serum interleukin-6, plasma ACTH and serum cortisol levels after systemic interferon-alpha administration. 855 63

The present study determined the plasma ACTH and corticosterone responses of the rat to acute local inflammation induced by the im injection of a small volume of turpentine. In response to tissue injury, ACTH and corticosterone concentrations rose rapidly, peaked at 1 h, and returned toward basal values by 3 h after turpentine injection. As acute inflammation developed, plasma interleukin-6 bioactivity increased significantly, and ACTH and corticosterone levels exhibited a secondary rise. These secondary responses were maximum 6-12 h after turpentine administration, persisted for 20-28 h, and were statistically significant regardless of the normal circadian variations in ACTH and corticosterone secretion. Injection of neutralizing anti-CRF antiserum 7 h after turpentine produced a complete reversal, whereas antiarginine vasopressin (anti-AVP) caused a partial (approximately 40%) inhibition, of inflammation-induced ACTH secretion. The cyclooxygenase inhibitor, ibuprofen (10 mg/kg, iv), like CRF antiserum, rapidly and completely reversed turpentine-induced ACTH secretion. In contrast, the nitric oxide synthase inhibitor, Nw-nitro-L-arginine methyl ester (30 mg/kg, iv), produced a significant enhancement of the ACTH response within 30 min of its injection. Measurement of plasma interleukin-6 bioactivity and fever showed that neither anti-CRF, anti-AVP, ibuprofen, nor Nw-nitro-L-arginine methyl ester acutely influenced the local inflammatory process itself, suggesting that these agents interacted directly with the hypothalamo-pituitary-adrenal axis. These data demonstrate that the ACTH response to local inflammation is mediated by synergistic actions of CRF and AVP, and that both stimulatory (PGs) and inhibitory (nitric oxide) intermediates regulate this response.
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PMID:Corticotropin-releasing factor, vasopressin, and prostaglandins mediate, and nitric oxide restrains, the hypothalamic-pituitary-adrenal response to acute local inflammation in the rat. 859 89

Two studies were conducted to investigate whether behavioral and physiological responses induced by administration of interleukin-1 beta (IL-1 beta) were also associated with changes in interleukin-6 (IL-6) and soluble IL-6 receptor levels (sIL-6R). Following intravenous injection of rhIL-1 beta, blood and cerebrospinal fluid (CSF) samples were collected from juvenile rhesus monkeys. Marked increases in IL-6 levels were evident at 1 h in both blood and intrathecal compartments. IL-1 beta also induced significant elevations in the release of ACTH and cortisol into the blood stream, and following high doses, the monkeys evinced signs of sickness behavior. The second study characterized the IL-beta dose-response relationship showing that these physiological changes were most evident at doses between 0.5 microgram and 1.0 microgram IL-1/kg body weight. Soluble IL-6 receptor concentration was also increased, but only in plasma. There was no detectable sIL-6R in CSF. The large release of IL-6 into CSF suggests that some behavioral symptoms may be due to intrinsic changes in central nervous system activity concomitant with the alterations in peripheral physiology.
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PMID:Interleukin-1 beta differentially affects interleukin-6 and soluble interleukin-6 receptor in the blood and central nervous system of the monkey. 896 7

Accumulating data indicate that interleukins can activate the hypothalamic-pituitary-adrenal (HPA) axis. We evaluated the effect of human recombinant interleukin-3 (IL-3) and interleukin-6 (IL-6) on cortisol secretion from adult human adrenocortical cells in primary culture. IL-3 and IL-6 (100 microg/L) equipotently stimulated basal cortisol secretion approximately 5-fold. The stimulatory effect was significant after 12 h (p<0.01) and maximum cortisol levels were induced after 48 h. In contrast to ACTH, which significantly induced cAMP levels in parallel to its steroidogenic effect, IL-3 or IL-6 had no significant effect on cAMP. Furthermore, we showed that specific inhibition of the cyclooxygenase pathway by indomethacin completely blocked the steroidogenic effect of IL-6 while the effect of IL-3 was not affected. In contrast, coincubation with nordihydroguaiaretic acid--a specific inhibitor of the lipoxygenase system--abolished IL-3 stimulated steroidogenesis but had no effect on IL-6 stimulated cortisol secretion. These findings indicate that IL-3 and IL-6 directly stimulate the steroidogenesis at the adrenal level through activation of different, cAMP-independent pathways. While the stimulatory effect of IL-6 on cortisol secretion from adult human adrenocortical cells seems to be mediated through the cyclooxygenase pathway, the effect of IL-3 on adrenocortical cortisol secretion is dependent on the lipoxygenase pathway.
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PMID:Interleukin-3 and interleukin-6 stimulate cortisol secretion from adult human adrenocortical cells. 911 22

Patients with malaria can have features of adrenal insufficiency. Because of the pathophysiological and clinical implications of an Addisonian state, the hypothalamic-pituitary-adrenocortical axis was assessed in nine Vietnamese adults with complicated malaria. A CRH test was performed on admission (in convalescence in five cases) and in six healthy controls. Basal plasma ACTH concentrations in the patients and controls were similar [median (range): 2.9 (0.2-9.7) vs. 3.5 (1.9-13.4) pmol/L, respectively; P > 0.1]. Serum cortisol levels were greater in the patients [882 (294-1682) vs. 190 (110-676) nmol/L; P < 0.01], but three (33%) had values within the control range. Basal serum corticosteroid-binding globulin concentrations were similar in patients and controls (P = 0.23). The post-CRH rise in plasma ACTH was attenuated in the patients [peak: 6.1 (0.9-23.2) vs. 14.5 (6.2-21.5) pmol/L in controls; P < 0.05]; basal and peak plasma ACTH correlated with plasma interleukin-6 in this group (rs > or = 0.60; P < or = 0.04). Serum cortisol responses to CRH were depressed in acute illness [peak 990 (394-1, 805) nmol/L or 10 (0-50%) above baseline vs. 500 (429-703) nmol/L or 160 (10-380%) in controls; P < 0.05]. The median estimated serum cortisol t1/2 was 4.6 h in the patients and 1.6 h in the controls. These data suggest that, relative to a normal stress response, primary and secondary adrenal insufficiency can occur in severe malaria but may be attenuated by increased circulating interleukin-6 concentrations and impaired cortisol metabolism. The benefits of stress-dose corticosteroid replacement are unknown but could be considered in hypoglycemic patients or those with a serum cortisol within or below the reference range.
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PMID:The hypothalamic-pituitary-adrenocortical axis in severe falciparum malaria: effects of cytokines. 928 38

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