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)

The mechanism by which the binding of growth hormone (GH) to its cell surface receptor elicits changes in gene transcription are largely unknown. The transcription factor Stat1/p91 has been shown to be activated by GH. Here we show that acute phase response factor or Stat3 f1p4an antigenically related protein), is also activated by GH. Stat3 has been implicated in the interleukin-6-dependent induction of acute phase response genes. GH promotes in 3T3-F442A fibroblasts the tyrosyl phosphorylation of a protein immunoprecipitated by antibodies to Stat3. This protein co-migrates with a tyrosyl phosphorylated protein from cells treated with leukemia inhibitory factor, a cytokine known to activate Stat3. Tyrosyl phosphorylated Stat3 is also observed in response to interferon-gamma. Stat3 is present in GH-inducible DNA-binding complexes that bind the sis-inducible element in the c-fos promoter and the acute phase response element in the alpha 2-macroglobulin promoter. The ability of GH to activate both Stat1 and Stat3 (i.e. increase their tyrosyl phosphorylation and ability to bind to DNA) suggests that gene regulation by GH involves multiple Stat proteins. Shared transcription factors among hormones and cytokines that activate JAK kinases provide an explanation for shared responses, while the ability of the different ligands to differentially recruit various Stat family members suggests mechanisms by which specificity in gene regulation could be achieved.
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PMID:Activation of acute phase response factor (APRF)/Stat3 transcription factor by growth hormone. 787 44

The JAK2 tyrosine kinase is known to associate with the receptors for growth hormone (GH) and erythropoietin (EPO) and with the interleukin-6 receptor signal transducing protein, gp130. Here we demonstrate that chimeric cytokine receptors which contain the cytoplasmic domain of the receptors for GH and EPO or for gp130 can form complexes with JAK2 when transiently co-expressed in HeLa cells. Mutational analyses of chimeras for the the GH and EPO receptors and gp130 demonstrated that box 1, a motif critical for cytokine receptor signal transduction, was required for the association of JAK2. Although JAK2 was capable of associating with all three of the chimeras, JAK1 co-precipitated only with the gp130 chimera. Association of JAK1 and JAK2 with cytokine receptor proteins, therefore, requires the highly conserved box 1 domain, but other sequences within the receptor proteins may influence the specificity of JAK binding. Mutational analysis of JAK2 revealed that multiple or complex protein sequences within JAK2 are required for association with cytokine receptors.
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PMID:The conserved box 1 motif of cytokine receptors is required for association with JAK kinases. 789 87

Inflammatory stimuli suppress constitutive hepatic expression of the CYP2C11 and CYP2C12 genes in male and female rat livers, respectively. We have shown previously that injection of interleukin-1 (IL1), but not interleukin-6 (IL6), to female rats also suppresses CYP2C12. In the present study, we examined the effects of these cytokines on CYP2C12 expression in rat hepatocyte cultures, and their in vivo effects on expression of multiple cytochrome P-450 (P450) gene products in male rat livers. IL1 suppressed the expression of CYP2C12 mRNA and protein in hepatocytes cultured on Matrigel in the presence of growth hormone. No consistent effect of IL6 was observed. Maximal suppression of CYP2C12 mRNA after 24 h of IL1 treatment reached 12 and 32% of control levels in two separate experiments. The approximate ED50 for IL1 was 5 ng/ml. CYP2C12 protein was suppressed to 28% of control levels as early as 12 h after IL1 treatment. Injection of IL1, low doses of dexamethasone, or both, in male rats produced decreases in total P450, and in CYP3A2 and CYP2C11 mRNA and protein expression similar to effects previously seen for CYP2C12 expression in females. CYP2E1 mRNA and protein was significantly suppressed only by the combination of IL1 and dexamethasone. IL6 treatment of male rats down-regulated the CYP2C11 and CYP2E1 mRNAs at a dose of 4.5 micrograms/kg, which was lower than that required to induce haptoglobin mRNA, a prototype acute phase gene product. CYP2C11 protein content of the microsomes was also decreased by IL6 treatment, with a slower time-course than for suppression of its mRNA. No significant effects of IL6 treatment were seen on CYP3A2 mRNA or CYP3A2/1 proteins. These results demonstrate that IL1 and IL6 treatments in vivo differentially affect subsets of P450 gene products in rat liver.
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PMID:Selective suppression of cytochrome P-450 gene expression by interleukins 1 and 6 in rat liver. 791 45

Interleukin-6 (IL-6) is a multifunctional cytokine which plays a role in the stimulation, inhibition, differentiation, and regulation of cell growth. IL-6 has been shown to act as an autocrine growth factor in several tumors, and is expressed by a variety of tumors. IL-6 also exhibits a regulatory role in the hypothalamo-pituitary axis. It is produced by both the hypothalamus and the pituitary, and it induces the secretion of anterior pituitary hormones. Because of the regulatory role of IL-6 in tumor growth and its involvement in the pituitary, we decided to evaluate IL-6 and IL-6 receptor expression in pituitary tumors. For this purpose we utilized complimentary cDNA probes specific for the IL-6 and IL-6 receptor mRNA, as well as monoclonal anti-IL-6 antibodies for immunohistochemical analysis. Our results show that the IL-6 gene is expressed in the normal pituitary tissue. However, the non-functioning and functioning pituitary tumors such as the prolactin and growth hormone secreting tumors express increased levels of the IL-6 gene. The IL-6 receptor gene was only expressed in the prolactin secreting and non-functioning pituitary tumors. These results show that the IL-6 and IL-6 receptor gene expression is enhanced in pituitary tumors, thus suggesting a possible role of IL-6 in the pathogenesis of these tumors.
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PMID:Interleukin-6 and interleukin-6 receptor gene expression in pituitary tumors. 796 88

Insulin-like growth factors are present in the circulation and are also synthesized by osteoblasts so that they may function both as systemic and local regulators of bone growth. Production of insulin-like growth factors in bone are under the control of parathyroid hormone, estrogen and growth hormone. Cytokines, such as interleukin-1, interleukin-6, tumor necrosis factor, stimulate osteoclastic bone resorption, and are under inhibitory control of estrogen. Bone loss associated with age and menopause may be due in part to removal of this inhibitory influence upon cytokines production.
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PMID:[Growth factors and cytokines in bone metabolism]. 796 72

The aging process is associated with significant declines in the levels of many hormones and trophic factors including estrogen, testosterone, growth hormone (somatropin, somatotropin) and insulin-like growth factor-1 (IGF-1, somatomedin-1, somatomedin-C). Since the classic age-related changes resemble the signs and symptoms of endocrine deficiency, it has been hypothesised that some of the negative effects of aging are due to these hormonal deficits. Consequently, the potential role of hormonal replacement in reversing the deleterious effects of aging deserves investigation. In old hypogonadal men, preliminary studies have shown that testosterone replacement not only improves libido but also significantly increases musculoskeletal mass and strength. However, adverse effects have included increases in haematocrit and prostate specific antigen. Similarly, short term studies with growth hormone replacement have shown substantial bodyweight gain, particularly in severely malnourished older adults, but longer studies have been limited by adverse effects such as gynaecomastia and carpal tunnel syndrome in a few people. Thus, though both testosterone and growth hormone may have potential roles for frailty syndromes in the elderly, long term clinical trials are needed to confirm these positive effects and assess their safety. On the other hand, the multiple beneficial effects of estrogen replacement in older women such as relieving acute menopausal symptoms and preventing postmenopausal osteoporosis are well recognised. Observational studies also suggest that estrogen may decrease cardiovascular disease. However, the optimum duration of treatment and the best way to administer this hormone are still unknown. Also, estrogen may be less effective in senile osteoporosis which primarily results from age-related bone loss. Traditionally, age-related bone loss has been attributed to impaired vitamin D activation and decreased calcium absorption. Thus, it was thought that such bone losses may be ameliorated by calcium supplementation. However, recent studies suggest that alterations in local factors affecting bone cell function may also be important in the pathogenesis of osteoporosis. An increase in potent bone resorbing factors, such as the cytokines interleukin-1 and interleukin-6, has been recently demonstrated in elderly patients with osteoporosis. In these patients, it has been suggested that there may also be a decrease in bone growth factors such as IGF-1 and transforming growth factor-beta. Accordingly, studies are underway to determine whether these factors may be useful in the prevention of osteoporosis. Other growth factors recently identified which may be important in aging include epidermal growth factor, nerve growth factor and fibroblast growth factor.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Trophic factors in aging. Should older people receive hormonal replacement therapy? 807 75

Random substitutions of amino acid 161-184 of human interleukin-6 (hIL-6) have been generated at the cDNA level using oligonucleotide-directed mutagenesis. Among the majority of the mutant proteins showing a reduced biological activity on murine hybridoma cells, only those having a substitution of Met161, Arg168, Arg179 or Met184, retained a tertiary structure similar to the IL-6 folding. These residues are thus probably involved in the interaction with the IL-6 receptor. However, the contacts established by Arg168 and Arg179 seem far more important for the biological activity. According to Bazan's model of cytokine folding and the receptor binding site on the fourth alpha-helix, based on growth hormone similarity, we propose that Arg168 and Arg179 are located on the exposed surface of this presumed helix.
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PMID:Mutagenesis of the human interleukin-6 fourth predicted alpha-helix: involvement of the Arg168 in the binding site. 818 15

Interleukin-6 (IL-6) was secreted by cultured cells of 7 out of 11 human pituitary adenomas that were examined. Interleukin-1 (IL-1) stimulated IL-6 release after a 24-h incubation period in five of the seven IL-6-secreting adenoma cultures and in all seven after 72 h. Tumour necrosis factor, interferon-gamma and epidermal growth factor did not significantly affect IL-6 secretion. Interleukin-1 failed to induce measurable IL-6 in the cultures that did not secrete IL-6 under basal conditions. Prostaglandin E2 did not influence basal IL-6 secretion and indomethacin did not inhibit IL-1-stimulated IL-6 release. In addition, pertussis toxin had no effect on IL-1-stimulated IL-6 release. The growth hormone (GH) secretory response to IL-1 varied, with stimulation in one GH-secreting adenoma culture, no significant effect in a second and inhibition in a third. Interleukin-1 did not significantly affect the release of prolactin, thyrotrophin, luteinizing hormone or follicle-stimulating hormone in any of the adenoma cultures. This study provides evidence that IL-1 is a stimulator of IL-6 release from cultured human pituitary adenoma cells that secrete IL-6. Stimulation of IL-6 release by IL-1 in these tumour cells is probably not mediated by prostaglandins or by a pertussis toxin-sensitive mechanism.
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PMID:Interleukin-1 stimulates the release of interleukin-6 from cultured human pituitary adenoma cells. 839 Nov 94

The CD30 surface molecule is a recently identified member of the tumor necrosis factor/nerve growth factor receptor superfamily. Within the cytoplasmic signal transducing domain, CD30 shares no significant homology to other members of this family. Signaling events engaged via CD30 are still unknown. We here identify the NF-kappabeta transcription factor as a target of the CD30-induced signal pathway in Hodgkin's disease (HD) cells. Exposure of HD cells to CD30 ligand induces release of interleukin-6 (IL-6) that can be duplicated by cross-linking HD-cells to an agonistic anti-CD30 specific monoclonal antibody (alphaCD30), but not by cross-linking to an isotype-identical irrelevant monoclonal antibody. Cross-linking of HD cells to alphaCD30 leads to enhanced accumulation of IL-6 mRNA in a time-dependent fashion resulting from transcriptional activation of the IL-6 promoter. Transient transfection assays using a series of deleted IL-6 promoter constructs linked to the human growth hormone gene as a reporter gene furthermore indicate that transcriptional activation of the IL-6 promoter requires the presence of an intact NF-kappabeta binding site. In addition, introduction of an NF-kappabeta binding site appeared to be sufficient to confer inducibility of an heterologous promoter on activation of CD30 in HD cells. Cross-linking of CD30 promotes rapid and transient binding activity of nuclear proteins to the NF-kappabeta recognition site of the IL-6 promoter. Supershift experiments using a series of monoclonal antibodies recognizing distinct members of the NF-kappaBeta transcription factor family furthermore indicate that in CD30 cross-linked HD cells p50, p65/Rel-A, and Rel-B are present, whereas the c-rel protein is not.
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PMID:Activation of Hodgkin cells via the CD30 receptor induces autocrine secretion of interleukin-6 engaging the NF-kappabeta transcription factor. 1101 49

Apoptosis is an important cellular process by which superfluous or unwanted cells are deleted from an organism during tissue remodeling and differentiation. Recent studies have demonstrated the role of this programmed cell death or "controlled cell suicide" in the physiological function of an organism. Suppression of apoptosis increases the susceptibility of an individual to malignancy whereas uncontrolled cell death is associated with degenerative diseases. Normal development of both female and male gonads is characterized by massive cell death. More than 99% of ovarian follicles endowed at early life are destined to undergo apoptosis and the exhaustion of these follicles serves as a "clock" for female reproductive senescence. In the testis, up to 75% of male germ cells also undergo apoptosis, perhaps as a mechanism to delete superfluous or defective germ cells. Gonadal cell apoptosis provides valuable models to study hormonal regulation of apoptosis. In the ovary, gonadotropins, estrogens, growth hormone, growth factors (IGFI, EGF/TGF-alpha, basic FGF), cytokine (interleukin-1 beta) and nitric oxide act in concert to ensure the survival of preovulatory follicles. In contrast, androgens, interleukin-6 and gonadal GnRH-like peptide are apoptotic factors. Developmental studies further indicate that fractions of endowed follicles are recruited throughout the reproductive life whereas most of the primordial follicles are "arrested" at the initial stage of development for a prolonged time. Because a transcriptional factor WT1 is expressed in high levels in follicles at early stages of development and because WT1 over-expression represses the promoter activity of inhibin-alpha gene, this nuclear protein may be important in the maintenance of follicles at early stages of development. Once a cohort of follicles is recruited to grow, it is destined to undergo apoptosis unless rescued by survival factors. After puberty onset and under gonadotropin stimulation, some of the growing antral follicles are "selected" to continue their final maturation and secrete high levels of estrogens to trigger ovulation. Following repeated cycles of recruitment, atresia or ovulation, the follicle reserve is exhausted, thus signaling the onset of reproductive senescence. Although the somatic granulosa cell is the major cell type undergoing apoptosis in the ovary, the germ cells in the testis also exhibit signs of apoptotic cell demise. In the testis, gonadotropins and androgens act as survival factors whereas exposure to elevated temperature in cryptorchid testes increases apoptosis. In the seasonally breeding hamster model, photoperiod-entrained regression and recrudescence of testis tissue serves as a unique natural model of apoptosis. With recent advances in our understanding of the cellular mechanism of apoptosis, including the elucidation of the Ced9/bc12 and Ced3/ICE family of proteins, further investigation of gonadal apoptosis may lead to a better understanding of gonadal degenerative disorders (such as premature ovarian failure and oligospermia), reproductive senescence and tumorigenesis. The gonadal model should also be valuable in studying the regulation of intracellular apoptosis genes by external hormonal signals.
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PMID:Gonadal cell apoptosis. 870 Oct 90

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