Disease relevance of IL6ST

• Oncostatin M, leukemia inhibitory factor, and interleukin 6 induce the proliferation of human plasmacytoma cells via the common signal transducer, gp130 [1].
• Epidermal growth factor receptor-independent constitutive activation of STAT3 in head and neck squamous cell carcinoma is mediated by the autocrine/paracrine stimulation of the interleukin 6/gp130 cytokine system [2].
• Our studies demonstrate that upon heterodimerization with the gp130 cytoplasmic region, the cytoplasmic parts of both LIFR and OSMR were critical for activation of an acute phase protein promoter in HepG2 hepatoma cells [3].
• METHODS: To define a role for gp130-RAPS in arthritis, a recombinant version was generated using a baculovirus expression system, and its activities were tested in vitro and in vivo [4].
• RESULTS: Gp130-RAPS was shown to bind with high affinity to the stable IL-6/sIL-6R complex, hyper-IL-6, and to effectively modulate leukocyte migration in murine acute peritonitis [4].

Psychiatry related information on IL6ST

• We quantitated interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R) and soluble form of the IL-6 signal-transducing protein gp130 (sgp130) in cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD) (n = 17) and control subjects (n = 18) using sensitive enzyme-linked immunosorbent assays (ELISA) [5].

High impact information on IL6ST

• Functional receptor complexes for this interleukin-6 family of cytokines share gp130 as a component critical for signal transduction [6].
• Although gp130 and its dimer partners possess no intrinsic tyrosine kinase domain, the dimerization of gp130 leads to activation of associated cytoplasmic tyrosine kinases and subsequent modification of transcription factors [6].
• Unlike cytokines sharing common beta and common gamma chains that mainly function in hematopoietic and lymphoid cell systems, the interleukin-6 family of cytokines function extensively outside these systems as well, e.g. from the cardiovascular to the nervous system, owing to ubiquitously expressed gp130 [6].
• Thus, cardiac myocyte apoptosis is a critical point in the transition between compensatory cardiac hypertrophy and heart failure. gp130-dependent cytokines may represent a novel therapeutic strategy for preventing in vivo heart failure [7].
• Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stress [7].

Chemical compound and disease context of IL6ST

• Proteasome inhibitor PS-341 abrogates IL-6 triggered signaling cascades via caspase-dependent downregulation of gp130 in multiple myeloma [8].
• 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 [9].
• Enhancement of gp130-mediated tyrosine phosphorylation of STAT3 and its DNA-binding activity in dexamethasone-treated AIDS-associated Kaposi's sarcoma cells: selective synergy between dexamethasone and gp130-related growth factors in Kaposi's sarcoma cell proliferation [10].
• To examine the molecular regulation of IL-6, IL-6 receptor, and signaling receptor gp130 during endotoxemia, nine healthy young volunteers received a bolus injection of lipopolysaccharide (LPS) on day 1 and saline on day 2 in a double blind, randomized, placebo-controlled trial [11].
• Prostaglandin E(2) stimulates prostatic intraepithelial neoplasia cell growth through activation of the interleukin-6/GP130/STAT-3 signaling pathway [12].

Biological context of IL6ST

• In a previous report, IL6ST was assigned to chromosomes 5 and 17 [13].
• They also emphasize that all myeloma cell growth factors reported to data involve an activation of the gp130 IL-6 transducer [14].
• In contrast, blocking the cytokine gp130 coreceptor abolished STAT3 tyrosine phosphorylation in HNSCC cells and that induced by the conditioned medium [2].
• In addition to its role in the generation of high affinity receptors, gp130 is required for signal transduction by these cytokines [15].
• Similarly to IL-6 and CNTF, gp130 is able to induce dimerization of the IL-11.IL-11Ralpha subcomplex, the result of which is the formation of a pentameric receptor complex [16].

Anatomical context of IL6ST

• The gp130 subunit alone confers low-affinity binding of OSM when expressed in COS-7 cells [17].
• Ciliary neurotropic factor, interleukin 11, leukemia inhibitory factor, and oncostatin M are growth factors for human myeloma cell lines using the interleukin 6 signal transducer gp130 [18].
• NNT-1/BSF-3 is a gp130 activator with B-cell stimulating capability [19].
• Since leukemia inhibitory factor functions as a cholinergic differentiation factor in nerve cells, as does ciliary neurotrophic factor, these results suggest that gp130 may also play a role in the nervous system [20].
• High glucose enhances interleukin-6-induced vascular endothelial growth factor 165 expression via activation of gp130-mediated p44/42 MAPK-CCAAT/enhancer binding protein signaling in gingival fibroblasts [21].

Associations of IL6ST with chemical compounds

• Tyrosine kinase activity was associated with dimerized but not monomeric gp130 protein [22].
• Substitution of serine for proline residues 656 and 658 in the cytoplasmic motif abolished tyrosine kinase activation and cellular responses but not homodimerization of gp130 [22].
• Engineered LIFR mutants in which either or both of these two residues were mutated to alanine were transfected in Ba/F3 cells already containing gp130 [23].
• Importantly, this effect on cytokine-induced gp130 signaling cascades may account, at least in part, for the remarkable preclinical sensitivity and clinical responses achieved in MM with PS-341 treatment [8].
• These observations add credence to the contention that increased production of gp130-utilizing cytokines and their receptors in pathological conditions like sex steroid deficiency is indeed responsible for not only the increased osteoclastogenesis, but also the increased osteoblastogenesis, and thereby for the increased rate of bone remodeling [24].

Physical interactions of IL6ST

• A corresponding gp130-binding site on IL-6 was exchanged with this epitope [25].
• In vitro immunoprecipitation experiments showed that sIL11Ralpha specifically binds IL-11 and that binding is enhanced by gp130 [16].
• Therefore, we conclude that the 150-kDa OM binding protein previously characterized in a variety of cell lines is gp130 [26].
• Here we show that the CBD of human gp130 can also bind in vitro to sCNTFR in the absence of CNTF [27].
• We found that Cdk9 interacts in vitro with the cytoplasmic region of gp130 and we succeded in reproducing this interaction in vivo [28].

Enzymatic interactions of IL6ST

• We found that gp130 fusion proteins were phosphorylated exclusively on Ser-782 by LIF- and growth factor-stimulated 3T3-L1 cell extracts [29].

Regulatory relationships of IL6ST

• IL-6-induced homodimerization of gp130 and associated activation of a tyrosine kinase [22].
• These data indicate that Jak family protein kinases may participate in IL-6 signaling and that APRF may be activated in a complex with gp130 [30].
• Together, our data reveal the crucial importance of overall vIL-6 structure and conformation for gp80-independent signaling and provide functional and physical evidence of the stabilization of vIL-6-induced gp130 signaling complexes by gp80 [31].
• IL-11 acts on cells expressing gp130 and the IL-11 receptor (IL-11R) alpha-subunit (IL-11Ralpha) [32].
• CT-1 activates gp130 and LIFR beta transducing components, as attested by analysing their tyrosine phosphorylation level [33].

Other interactions of IL6ST

• Binding of IL-6 to IL-6R induced disulfide-linked homodimerization of gp130 [22].
• Protein kinases of the Jak family were also rapidly tyrosine phosphorylated, and both APRF and Jak1 associated with gp130 [30].
• These cytokines initiate signaling by inducing either homodimerization of gp130 or heterodimerization of gp130 with leukemia-inhibitory factor receptor beta components [34].
• Our results indicate that the myeloma cell growth factor activity of IL-10 was abrogated by an antibody to the gp 130 IL-6 transducer, indicating that it was mediated through one of the gp 130-activating cytokines [14].
• Interestingly, binding of LIF to type 1 receptor was not affected, corroborating the notion that in this case gp130 mostly behaves as a converter protein rather than a binding receptor [35].

Analytical, diagnostic and therapeutic context of IL6ST

• Co-precipitation of gp130-associated proteins, flow cytometry, polymerase chain reaction, and tyrosine phosphorylation analyses allowed the characterization of both types of OSM receptors expressed on the surface of different cell lines [36].
• A single intraarticular injection of gp130-RAPS suppressed chronic antigen-induced arthritis in association with a reduction in local activation of signal transducer and activator of transcription 3 [4].
• Examination of 50 clinical samples of malignant breast tissue by RT-PCR showed a similar pattern of expression of gp130 associated receptors [37].
• PCR and Northern blot analysis only identified one gp130 membrane mRNA, suggesting that the soluble form of gp130 is generated by proteolytic cleavage [38].
• Receptor mobility shift assays confirmed that the new isoform formed a stable complex with IL-6Ralpha; however, no interaction with IL-6Rbeta was observed [39].

References