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)

STAT3 (signal transducer and activator of transcription 3) is a key transcription factor mediating the signals for a variety of cytokines, including interleukin-6 (IL-6). The Stat3 gene itself is activated by IL-6 signals. We show that the region of the signal-transducing subunit, gp130, essential for STAT3 activation, is also required for activation of the Stat3 gene. To elucidate the mechanisms activating the Stat3 gene, we identified an IL-6 response element (IL-6RE) in the Stat3 gene promoter containing both a low affinity STAT3-binding element and a cAMP-responsive element (CRE). Electrophoretic mobility shift assays showed that IL-6 induced a slowly migrating complex on the IL-6RE containing a STAT3 homodimer and an unidentified CRE-binding protein. With the combination of transient transfection assays using mutant Stat3 promoter-reporter constructs and electrophoretic mobility shift assays, we found that the formation of a slowly migrating complex was required for full activation of the Stat3 gene. Thus, STAT3 activates the Stat3 gene in cooperation with an unidentified CRE-binding protein. This regulatory mechanism is similar to that of the junB gene, which is activated by IL-6 through the junB IL-6RE, which contains a low affinity STAT3-binding site and a CRE-like site.
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PMID:Autoregulation of the Stat3 gene through cooperation with a cAMP-responsive element-binding protein. 949 31

Uteroglobin (UG) is a steroid-inducible, multifunctional, secreted protein with antiinflammatory and antichemotactic properties. Recently, we have reported a high affinity UG-binding protein (putative receptor), on several cell types, with an apparent molecular mass of 190 kDa (Kundu, G. C., Mantile, G., Miele, L., Cordella-Miele, E., and Mukherjee, A. B. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 2915-2919). Since UG is a homodimer in which the 70 amino acid subunits are connected by two disulfide bonds, we sought to determine whether UG monomers also interact with the 190-kDa UG-binding protein and if so, whether it has the same biological activity as the dimer. Surprisingly, we discovered that in addition to the 190-kDa species, another protein, with an apparent molecular mass of 49 kDa, binds reduced UG with high affinity and specificity. Both 49- and 190-kDa proteins are readily detectable on nontransformed NIH 3T3 and some murine cancer cells (e. g. mastocytoma, sarcoma, and lymphoma), while lacking on others (e.g. fibrosarcoma). Most interestingly, pretreatment of the cells, which express the binding proteins, with reduced UG dramatically suppresses extracellular matrix (ECM) invasion, when such treatment had no effect on fibrosarcoma cells that lack the UG-binding proteins. Tissue-specific expression studies confirmed that while both 190- and 49-kDa UG-binding proteins are present in bovine heart, spleen, and the liver, only the 190-kDa protein is detectable in the trachea and in the lung. Neither the 190-kDa nor the 49-kDa protein was detectable in the aorta. Purification of these binding proteins from bovine spleen by UG-affinity chromatography and analysis by SDS-polyacrylamide gel electrophoresis followed by silver staining identified two protein bands with apparent molecular masses of 40 and 180 kDa, respectively. Treatment of the NIH 3T3 cells with specific cytokines (i.e. interleukin-6) and other agonists (i.e. lipopolysaccharide) caused a substantially increased level of 125I-UG binding but the same cells, when treated with platelet-derived growth factor, tumor necrosis factor-alpha, interferon-gamma, and phorbol 12-myristate 13-acetate, did not alter the UG binding. Taken together, these findings raise the possibility that UG, through its binding proteins, plays critical roles in the regulation of cellular motility and ECM invasion.
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PMID:Uteroglobin (UG) suppresses extracellular matrix invasion by normal and cancer cells that express the high affinity UG-binding proteins. 971 16

Interleukin-6 (IL-6) and ciliary neurotrophic factor (CNTF) are "4-helical bundle" cytokines of the IL-6 type family of neuropoietic and hematopoietic cytokines. IL-6 signals by induction of a gp130 homodimer (e.g. IL-6), whereas CNTF and leukemia inhibitory factor (LIF) signal via a heterodimer of gp130 and LIF receptor (LIFR). Despite binding to the same receptor component (gp130) and a similar protein structure, IL-6 and CNTF share only 6% sequence identity. Using molecular modeling we defined a putative LIFR binding epitope on CNTF that consists of three distinct regions (C-terminal A-helix/N-terminal AB loop, BC loop, C-terminal CD-loop/N-terminal D-helix). A corresponding gp130-binding site on IL-6 was exchanged with this epitope. The resulting IL-6/CNTF chimera lost the capacity to signal via gp130 on cells without LIFR, but acquired the ability to signal via the gp130/LIFR heterodimer and STAT3 on responsive cells. Besides identifying a specific LIFR binding epitope on CNTF, our results suggest that receptor recognition sites of cytokines are organized as modules that are exchangeable even between cytokines with limited sequence homology.
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PMID:Receptor recognition sites of cytokines are organized as exchangeable modules. Transfer of the leukemia inhibitory factor receptor-binding site from ciliary neurotrophic factor to interleukin-6. 1020 5

HM1.24 antigen has been identified as a surface molecule preferentially expressed on terminally differentiated B cells, and its overexpression is observed in multiple myeloma cells. The HM1.24 antigen is, therefore, expected as a most potent target molecule for antibody-based immunotherapy for multiple myeloma. Here, we have identified the cDNA for human HM1.24 antigen and also analyzed its gene structure including the promoter region. The HM1.24 antigen is a type II membrane glycoprotein, which has been reported as a bone marrow stromal cell surface antigen BST2, and may exist as a homodimer on myeloma cell surface. Although a reason for the overexpression in myeloma cells is not understood, very interestingly, the promoter region of the HM1.24 gene has a tandem repeat of three cis elements for a transcription factor, STAT3, which mediates interleukin-6 (IL-6) response gene expression. Since IL-6 is a differentiation factor for B cells, and known as a paracrine/autocrine growth factor for multiple myeloma cells, the expression of HM1.24 antigen may be regulated by the activation of STAT3. Importantly, a humanized anti-HM1.24 antibody effectively lysed the CHO transformants which expressed HM1.24 antigen as high as human multiple myeloma cells, but not the cells with lower antigen expression. This evaluation shows that ADCC heavily depends on the expression level of target antigens and, therefore, the immunotherapy targeting the HM1.24 antigen should have a promising potential in clinical use.
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PMID:Molecular cloning and characterization of a surface antigen preferentially overexpressed on multiple myeloma cells. 1032 29

Interleukin-6 (IL-6) exhibits multiple biologic activities such as regulation of immunological responses and hematopoiesis, promotion of acute inflammation, and stimulation of some malignant and non-malignant cell growth. The IL-6 receptor system consists of an IL-6 specific binding molecule, IL-6R and a signal transducer, gp130. Following gp130 dimerization, IL-6 activates multiple signaling pathways (Ras dependent MAPk cascade, STAT1-STAT3 heterodimer pathway, and STAT3 homodimer pathway). Several other cytokines including oncostatin M, IL-11, leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF) and cardiotropin-1 (CT-1) use gp130 as a common signal transducing molecule and therefore have similar biological activities. Two major in vivo functions of IL-6 are reported. Firstly, IL-6 acts as a growth factor of some malignant and non-malignant cells such as malignant plasma cells in multiple myeloma, mesangial cells in the kidney, and keratinocytes. Secondly, IL-6 mediates inflammatory and immune responses in rheumatoid arthritis, Castleman disease, psoriasis, cardiac myxoma, cachexia, and other inflammatory conditions. Recently, a humanized anti-IL-6 receptor antibody was developed. Neutralization of IL-6 activity by the humanized anti-IL-6 receptor antibody may be a new therapeutic approach for IL-6 related diseases such as multiple myeloma, Castleman disease and rheumatoid arthritis.
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PMID:[Advances in interleukin-6 therapy]. 1034 5

This study was aimed at an assessment of the role of oxygen-derived free radicals, cytokines and endogenous cholecystokinin (CCK) in the pathogenesis of L-arginine (Arg)-induced acute pancreatitis in rat. We measured the levels of malonyl dialdehyde (MDA), glutathione peroxidase (GPx), catalase and superoxide dismutase (Mn- and Cu, Zn-SOD) in pancreatic tissue, the serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and CCK, and evaluated the protective effect of the xanthine oxidase inhibitor allopurinol and a novel CCK receptor antagonist KSG-504. Acute pancreatitis was induced in male Wistar rats by injecting 2x 250 mg/100 g body weight of Arg intraperitoneally in an 1-h interval, as a 20% solution in 0.15 M NaCl. Control rats received the same quantity of glycine. 200 mg x kg(-1) allopurinol 30 min before the first Arg treatment or 50 mg x kg(-1) KSG-504 30 min before and 6, 18 and 36 h after the first Arg injection was administered subcutaneously. Rats were killed at 6, 12, 24 and 48 h following Arg administration, and acute pancreatitis was confirmed by a serum amylase level elevation and typical inflammatory features observed microscopically. The serum level of amylase reached the peak level at 24 h after the Arg injection (30,800 +/- 3,813 versus 6,382 +/- 184 U x L(-1) in the control) and normalized at 48 h. The tissue concentration of MDA was significantly elevated at 24 h, and reached the peak value at 48 h (5.00 +/- 1.75 versus 0.28 +/- 0.05 nM x mg(-1) protein in the control). The catalase and Mn-SOD activities were significantly decreased throughout the study, while the GPx activity was significantly reduced at 6 and 12 h, and the Cu, Zn-SOD activity was significantly lower at 12 h after the Arg injection as compared with the controls. Both the TNF-alpha and the IL-6 levels were already elevated significantly at 12 h and peak at 24 h versus the controls (19.1 +/- 7.9 U x mL(-1) and 57.6 +/- 11.2 pg x mL(-1) versus 3.1 +/- 0.8 U x mL(-1) and 15.2 +/- 3.1 pg x mL(-1), respectively). No significant changes in plasma CCK levels were observed. Allopurinol treatment markedly reduced the serum amylase elevation (12.631 +/- 2.257 U x L(-1) at 24 h), prevented the increase in tissue MDA concentration (0.55 +/- 0.09 nM x mg(-1) protein at 48 h) and significantly ameliorated the pancreatic edema, necrosis and inflammation at 48 h after Arg administration. KSG-504 administration did not exert any beneficial effect on the development of histopathological changes neither modified the serum amylase or cytokine levels. Oxygen-derived free radicals and cytokines are involved, while endogenous CCK does not seem to play a role in the pathogenesis of Arg-induced acute pancreatitis.
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PMID:The pathogenesis of L-arginine-induced acute necrotizing pancreatitis: inflammatory mediators and endogenous cholecystokinin. 1076 88

-Cardiotrophin-1, an interleukin-6-related cytokine, stimulates the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway and induces cardiac myocyte hypertrophy. In this study, we demonstrate that cardiotrophin-1 induces cardiac myocyte hypertrophy in part by upregulation of a local renin-angiotensin system through the JAK/STAT pathway. We found that cardiotrophin-1 increased angiotensinogen mRNA expression in cardiac myocytes via STAT3 activation. Tyrosine phosphorylation of STAT3 by cardiotrophin-1 treatment resulted in STAT3 homodimer binding to the St-domain in the angiotensinogen gene promoter, which lead to promoter activation in a transient transfection assay. Cardiotrophin-1-induced STAT3 tyrosine phosphorylation and binding to the St-domain were suppressed by AG490, a specific JAK2 inhibitor, which also attenuated cardiotrophin-1-stimulated angiotensinogen promoter activity. Cardiotrophin-1 did not activate the angiotensinogen gene promoter that contained a substitution mutation within the St-domain. Finally, losartan, an angiotensin II type 1 receptor antagonist, significantly attenuated cardiotrophin-1-induced hypertrophy of neonatal rat cardiac myocytes. Angiotensin II is known to induce cardiac myocyte hypertrophy by activating the G-protein-coupled angiotensin II type 1 receptor. Our results suggest that upregulation of angiotensinogen and angiotensin II production contribute to cardiotrophin-1-induced cardiac myocyte hypertrophy and emphasize an important interaction between G-protein-coupled and cytokine receptors.
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PMID:Cardiotrophin-1 increases angiotensinogen mRNA in rat cardiac myocytes through STAT3 : an autocrine loop for hypertrophy. 1085 62

In order to determine the role of the neuropoietic cytokine interleukin-6 (IL-6) during the first 3 weeks after a focal brain injury, we examined the inflammatory response, oxidative stress and neuronal survival in normal and interleukin-6-deficient (knockout, IL-6KO) mice subjected to a cortical freeze lesion. In normal mice, the brain injury was followed by reactive astrogliosis and recruitment of macrophages from 1 day postlesion (dpl), peaking at 3-10 dpl, and by 20 dpl the transient immunoreactions were decreased, and a glial scar was present. In IL-6KO mice, the reactive astrogliosis and recruitment of macrophages were decreased throughout the experimental period. The expression of the antioxidant and anti-apoptotic factors metallothionein I+II (MT-I+II) was increased prominently by the freeze lesion, but this response was significantly reduced in the IL-6 KO mice. By contrast, the expression of the antioxidants Cu/Zn-superoxide dismutase (Cu/Zn-SOD), Mn-SOD, and catalase remained unaffected by the IL-6 deficiency. The lesioned mice showed increased oxidative stress, as judged by malondialdehyde (MDA) and nitrotyrosine (NITT) levels and by formation of inducible nitric oxide synthase (iNOS). IL-6KO mice showed higher levels of MDA, NITT, and iNOS than did normal mice. Concomitantly, in IL-6KO mice the number of apoptotic neurons was significantly increased as judged by TUNEL staining, and regeneration of the tissue was delayed relative to normal mice. The changes in neuronal tissue damage and in brain regeneration observed in IL-6KO mice are likely caused by the IL-6-dependent decrease in MT-I+II expression, indicating IL-6 and MT-I+II as neuroprotective factors during brain injury.
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PMID:Impaired inflammatory response and increased oxidative stress and neurodegeneration after brain injury in interleukin-6-deficient mice. 1110 68

1. M40403 is a low molecular weight, synthetic manganese containing superoxide dismutase mimetic (SODm) that removes superoxide anions (*O2-) without interfering with other reactive species known to be involved in inflammatory responses (e.g. nitric oxide, NO and peroxynitrite, ONOO-). 2. As such, M40403 represents an important pharmacological tool to dissect the roles of *O2- in acute and chronic inflammation. For this purpose, the pharmacological profile of M40403 was evaluated in carrageenan-induced pleurisy. 3. Injection of carrageenan into the pleural cavity of rats elicited an acute inflammatory response characterized by: fluid accumulation in the pleural cavity which contained a large number of neutrophils (PMNs) as well as an infiltration of PMNs in lung tissues and subsequent lipid peroxidation, and increased production of nitrite/nitrate (NOx), prostaglandin E2 (PGE2), tumour necrosis factor alpha, (TNFalpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and interleukin-10 (IL-10). 4. All parameters of inflammation were attenuated by M40403 except for NOx, PGE2 and IL-10 which remained unaltered. Furthermore, carrageenan induced an upregulation of the adhesion molecules ICAM-1 and P-selectin, as well as nitrotyrosine and poly (ADP-ribose) synthetase (PARS) as determined by immunohistochemical analysis of lung tissues. 5. The degree of staining for the ICAM-1, P-selectin, nitrotyrosine and PARS was reduced by M40403. 6. These results clearly indicate that *O2- plays a critical role in the development of the inflammatory response by altering key components of the inflammatory cascade. Therefore, synthetic enzymes of SOD such as M40403, offers a novel therapeutic approach for the management of various inflammatory diseases where these radicals have been postulated to play a role.
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PMID:Pharmacological manipulation of the inflammatory cascade by the superoxide dismutase mimetic, M40403. 1118 22

The role of interleukin-6 in hippocampal tissue damage after injection with kainic acid, a rigid glutamate analogue inducing epileptic seizures, has been studied by means of interleukin-6 null mice. At 35mg/kg, kainic acid induced convulsions in both control (75%) and interleukin-6 null (100%) mice, and caused a significant mortality (62%) only in the latter mice, indicating that interleukin-6 deficiency increased the susceptibility to kainic acid-induced brain damage. To compare the histopathological damage caused to the brain, control and interleukin-6 null mice were administered 8.75mg/kg kainic acid and were killed six days later. Morphological damage to the hippocampal field CA1-CA3 was seen after kainic acid treatment. Reactive astrogliosis and microgliosis were prominent in kainic acid-injected normal mice hippocampus, and clear signs of increased oxidative stress were evident. Thus, the immunoreactivity for inducible nitric oxide synthase, peroxynitrite-induced nitration of proteins and byproducts of fatty acid peroxidation were dramatically increased, as was that for metallothionein I+II, Mn-superoxide dismutase and Cu/Zn-superoxide dismutase. In accordance, a significant neuronal apoptosis was caused by kainic acid, as revealed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling and interleukin-1beta converting enzyme/Caspase-1 stainings. In kainic acid-injected interleukin-6 null mice, reactive astrogliosis and microgliosis were reduced, while morphological hippocampal damage, oxidative stress and apoptotic neuronal death were increased. Since metallothionein-I+II levels were lower, and those of inducible nitric oxide synthase higher, these concomitant changes are likely to contribute to the observed increased oxidative stress and neuronal death in the interleukin-6 null mice. The present results demonstrate that interleukin-6 deficiency increases neuronal injury and impairs the inflammatory response after kainic acid-induced seizures.
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PMID:Interleukin-6 deficiency reduces the brain inflammatory response and increases oxidative stress and neurodegeneration after kainic acid-induced seizures. 1118 44


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