Disease relevance of IL6

• An IL6 promoter polymorphism is associated with a lifetime risk of development of Kaposi sarcoma in men infected with human immunodeficiency virus [1].
• The IL6 polymorphism was significantly associated with breast cancer [2].
• Additionally, we found that an IL8 promoter polymorphism had a protective effect for lung cancer in female subjects, whereas an IL6 promoter polymorphism was only associated with risk of squamous cell carcinoma [3].
• Our data suggest that variant alleles of both IL6 and CHIT could influence susceptibility to infection with Gram-negative bacteria in children undergoing therapy for AML [4].
• Genetic variations in IL6 associate with intervertebral disc disease characterized by sciatica [5].
• Elevated PB IL-6 levels correlated with features of high-risk neuroblastoma and poor prognosis in this population [6].
• The rs1800795 IL-6 promoter SNP is an independent prognostic factor for EFS and OS in high-risk neuroblastoma patients [7].

Psychiatry related information on IL6

• It appears that BSF2/IL-6 plays an essential role in the host defense mechanisms against infections, inflammation, and injury [8].
• The capacity for sIL-6R to enhance IL-6 function and broaden the IL-6 target cell population in the brain has implications for the regulation of beta-APP expression in disease states such as Alzheimer's disease where elevations in brain IL-6 levels have been reported [9].
• Depressive symptoms following IFNalpha treatment may be secondary to cytokine induction, including that of IL-6 [10].
• CONCLUSIONS: The results suggest that PTSD is associated with increased IL-6 signaling [11].
• Our results, which show for the first time strikingly increased CSF levels of TNF-alpha but not of TNF-beta, IL-1beta or IL-6 in AD and VAD, may form a conceptual framework for further studies of neuroprotective mechanisms in dementias [12].
• Among older adults free of clinical cardiovascular disease, specific IL-6 promoter and apo E alleles appeared to confer positive associations of alcohol consumption with IL-6 concentrations [13].

High impact information on IL6

• A signaling adapter function for alpha6beta4 integrin in the control of HGF-dependent invasive growth [14].
• Like HGF, InlB binds to the extracellular domain of Met and induces "scattering" of epithelial cells [15].
• Treatment of mammalian cells with InlB protein or infection with L. monocytogenes induces rapid tyrosine phosphorylation of Met, a receptor tyrosine kinase (RTK) for which the only known ligand is Hepatocyte Growth Factor (HGF) [15].
• In contrast, we observed that p91 is not tyrosine phosphorylated in response to IL-6 [16].
• Here, we report the existence in the hepatocyte growth factor/scatter factor (HGF/SF) receptor of a multifunctional docking site made of the tandemly arranged degenerate sequence YVH/NV [17].

Chemical compound and disease context of IL6

• Plasma from 10 patients (6 died) infected with Neisseria meningitidis previously shown to contain high levels of native lipopolysaccharide (LPS) (median 2,700 pg/ml), TNF-alpha, IL-6, IL-8, and complement activation products, had a low net spontaneous inflammatory capacity on the monocytes [18].
• These results demonstrate induction of HIV-1 by IL-18 in a monocyte target associated with an intermediate role for TNF and IL-6, activation of p38 mitogen-activated protein kinase, and nuclear translocation of NF-kappaB [19].
• The interleukin 6/glycoprotein 130/signal transducer and activator of transcription 3 (IL-6/gp130/STAT3) pathway has been reported to play an important role in the pathogenesis of multiple myeloma (MM) and for survival of MM cells [20].
• Mutation of the NF-kappaB and AP-1 sites drastically reduces IL-6 promoter activity in both androgen-independent prostate cancer cell lines [21].
• In conclusion, our results suggest that aspirin and NS-398 inhibit HGF-induced invasiveness of HepG2 human hepatoma cells through ERK1/2 [22].

Biological context of IL6

• Our results show that IL6 promoter genotypes associated with altered gene expression are risk factors for development of KS [1].
• Homozygotes for IL6 allele G, associated with increased IL6 production, were overrepresented among patients with KS (P =.0046), whereas allele C homozygotes were underrepresented (P =.0062) [1].
• U.v.-cross linking study revealed that JRE-IL6 bound a 90 kDa protein, corresponding to Stat3, and a 36 kDa protein, most likely a CRE-like site binding protein(s) [23].
• The expression of 'insulin-resistance genes' HSD11B1 and IL6 was increased by insulin in the insulin-resistant group, but insulin failed to increase HSD11B1 expression in the insulin-sensitive group [24].
• CONCLUSIONS: Although polymorphisms within the IL1 gene cluster do not seem to influence breast cancer risk or phenotype, presence of the -174C IL6 allele increases the risk of breast cancer in Caucasian women in a dose-dependent fashion [2].

Anatomical context of IL6

• This study demonstrates that LMP1 expression in carcinoma cell lines and SV40-transformed keratinocytes results in induction of the pleiotropic cytokine interleukin 6 (IL6), an effect which is also observed upon CD40 ligation [25].
• OBJECTIVES: To assess the potential of the donor heart to respond to interleukin-6 (IL6), the present study investigated the expression of IL6 receptor components in the myocardium of donor hearts before transplantation [26].
• While IL6 was mainly expressed by myocytes, both receptor components were preferentially found mainly on interstitial cells [26].
• Right ventricles of failing hearts showed IL6, IL6R and gp130 mRNA levels comparable with those found in donor hearts [26].
• On the other hand, it appears that IL-6R expression by primary hepatocytes is sufficient and that circulating sIL-6R is unlikely to play a significant role in the modulation of IL6 effects [27].

Associations of IL6 with chemical compounds

• CONCLUSIONS/INTERPRETATION: Homocysteine upregulates the MMP-TIMP pathway and IL6 release, the effect being stronger in the presence of high glucose [28].
• METHODS: We investigated the relationship of polymorphisms in 6 cytokine genes associated with inflammation-interleukin (IL)1alpha, IL1beta, IL2, IL6, tumor necrosis factor (TNF), and lymphotoxin alpha (LTA)-with spontaneous preterm and SGA birth in a nested case-control study drawn from a prospective pregnancy cohort [29].
• The reappearance of IL6-binding sites at the cell surface required greater than 8 h and was sensitive to cycloheximide, suggesting that gp80 is not recycled after internalization [30].
• Thus, a general first step in IL-6-related cytokine signaling may be the dimerization of signal-transducing molecules and activation of associated tyrosine kinases [31].
• The median levels of PCA, TNF-alpha, and IL-6 were 5, 0, and 4%, respectively, of the monocyte activities induced by normal plasma boosted with purified N. meningitidis (Nm)-LPS (2,500 pg/ml; net LPS-boosted capacity, 100%) [18].
• These data suggest that the stimulatory effects of insulin on IL-6 release involve several interrelated components: transcription, intracellular releasable pool, and secretion, which are differentially regulated and, thus, determine the size of the releasable pool of IL-6 [32].
• Further investigations into the signaling mechanisms regulating IL-6 production led to the discovery that the Tec kinase bone marrow tyrosine kinase gene in chromosome X (Bmx) regulates Toll-like receptor-induced IL-6 production [33].
• Without exogenous IL-6/sIL-6R, injury plus TNFalpha exposure up-regulated chondrocyte production of IL-6, but incubation with the IL-6-blocking Fab significantly reduced proteoglycan degradation [34].
• Bicalutamide showed an inhibitory effect on IL-6-regulated growth in vivo [35].

Physical interactions of IL6

• The TNF-alpha mediated transcriptional activation of a chloramphenicol acetyltransferase (CAT) plasmid containing three copies of the -72 kappa B binding site from the IL-6 promoter was abrogated by PDTC [36].
• We studied the capacity of these mutants to form an IL-6/IL-6R complex and their ability to transduce the signal [37].
• A corresponding gp130-binding site on IL-6 was exchanged with this epitope [38].
• Recently, we showed that the magnitude of Stat3 binding to three IL-6 motifs on the human gammaFBG promoter correlates negatively with their functional activity in hepatocytes, although these cis-elements are critical for promoter activity [39].
• Moreover, titration of sgp130 with OM inhibits the formation of a ternary complex comprising IL-6, sIL-6R alpha, and sgp130 [40].

Enzymatic interactions of IL6

• Upon activation of signaling by IL-6 or orthovanadate the respective Tyr-phosphorylated STAT species were now also observed in the membrane raft fraction but in a form deficient in DNA binding [41].
• RESULTS: We report that NSCLC cells overexpressing COX-2 (COX-2-S) have increased IL-6 and phosphorylated STAT3 expression compared with control cells [42].
• Also p27 protein accumulated which coincided with the disappearance of hyperphosphorylated retinoblastoma protein in three human melanoma cell lines sensitive to IL-6-type cytokines [43].
• Western blot analysis demonstrated that IL-6 indeed increased the activation of phosphorylated MEK and p38 MAPK in GH3 cells [44].
• METHODS: The effect of IL-6 on apoptosis induced by androgen deprivation in LNCaP cells was examined by cell death ELISA and Western blot using cleaved poly (ADP-ribose) polymerase (PARP) and caspase-9, as well as Bcl-xL and phosphorylated Bad [45].

Co-localisations of IL6

• Furthermore, FKHR and STAT3 were shown to coimmunoprecipitate and to colocalize in the nuclear regions of IL-6-treated HepG2 cells [46].

Regulatory relationships of IL6

• IL-6-induced homodimerization of gp130 and associated activation of a tyrosine kinase [31].
• However, significantly more IL-7 than IL-1 beta was required to induce detectable levels of IL-6 [47].
• In contrast to the low concentrations of IL-7 required to stimulate T cell growth and differentiation (as low as 0.1 ng/ml), relatively high concentrations of IL-7 were necessary to induce IL-6 secretion by monocytes (at least 10 ng/ml) [47].
• IL-6 induced STAT3 phosphorylation and activation in HOSE cells; STAT3 was constitutively activated in OVCA cells [48].
• The IL-8-induced inhibition was counteracted by IL-6 and tumor necrosis factor-alpha (TNF-alpha) and was blocked by anti-IL-8 monoclonal antibody (MoAb) [49].
• Vice versa, inactivation of IL-6 autocrine loop had no influence on apoptosis levels in the absence of Mcl-1, thus suggesting this molecule as a mediator of the survival action of IL-6 [50].
• IL-6 treatment triggered Notch-3-dependent upregulation of the Notch ligand Jagged-1 and promotion of MS and MCF-7-derived spheroid growth [51].

Other interactions of IL6

• RESULTS--Mean serum IL-6 levels, but not IL-1 beta or tumor necrosis factor-alpha levels, correlated with organ failure (r = 0.79, P < .001) [52].
• Subsequently, the plasma is removed, medium added, and procoagulant activity (PCA) and secretion of tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) measured after 18-h incubation [18].
• Moreover, addition of IL-5 or IL-6 did not reverse IL-8-induced inhibition of IgE production [53].
• These results indicate that histamine enhanced IgE and IgG4 production by increasing endogenous IL-6 and IL-10 production via H1 and H3 receptors, respectively [54].
• Addition of anti-mu potentiated the effect of IL-4 on IL-6 production [55].
• IL-6 induction was mediated via Toll-like receptor 2 (TLR2) and lead to increased B-cell proliferation in vitro [56].
• Response rates to HCV-specific treatment are higher in HCV/HIV-positive patients carrying the IL-6 HP genotype, which might be because of IL-6 mediated STAT3 activation [57].
• Only partial inhibition by dominant-negative AKT and no inhibitory effect of IKKalphaT23A was observed on an IL-6 promoter-specific NFkappaB site in contrast to significant inhibitory effects on the AP-1 site [58].

Analytical, diagnostic and therapeutic context of IL6

• CONCLUSIONS: The expression of the IL6 receptor components in the donor heart before transplantation establishes the condition sine qua non for the response of the donor heart to circulating IL6 [26].
• This mechanism may explain the close association of elevated IL6 serum levels to acute cardiac allograft dysfunction in the early perioperative period [26].
• Chromatin immunoprecipitation revealed direct interaction between the IL6 promoter and the C/EBP beta protein [59].
• DNA probes to the human interleukin 4 (IL4) and interleukin 6 (IL6) genes have been used for in situ hybridization to normal human chromosomes and Southern blot analysis of a series of mouse-human hybrid cell lines [60].
• We measured VEGF, IL1 alpha and IL6 levels by ELISA [61].

References