Regular ArticleCytokines oncostatin M and interleukin 1 regulate the expression of the IL-6 receptor (gp80, gp130)
Abstract
The steady-state mRNA levels of the interleukin 6 receptor (IL-6R, gp80) and its signal transducing molecule, gp130, were examined in the rat hepatoma cell line, H-35, stimulated by cytokines IL-6, IL-1, oncostatin M (OSM) and/or Dexamethasone (Dex). In contrast to our previous findings in vivo [Geisterferet al., 1993,Cytokine, 5:1] in vitro Dex seemed to be the major stimulator of IL-6R mRNA expression, whereas IL-6 seemed to have little effect on the expression of its own receptor mRNA levels. However, the presence of other cytokines influenced the Dex mediated stimulation of IL-6R expression. OSM stimulated IL-6R mRNA levels. At 6 h, cells stimulated with OSM showed a 2.1-fold increase in IL-6R mRNA expression. This stimulation was additive with the Dex-mediated stimulation of IL-6R mRNA levels. In contrast, IL-1 inhibited the Dex-mediated stimulation of IL-6R mRNA. At the same time, IL-1 stimulated the presence of a second smaller mRNA transcript. This mRNA species contained the extracellular domain but lacked both the transmembrane and cytoplasmic domains of the IL-6R, suggesting alternate splicing, possibly coding for a soluble form of gp80. Unlike the gp80 IL-6R molecule, the expression of the gp130 molecule normally expressed as two species of mRNA was not regulated to any major extent in vitro. IL-1 and OSM stimulated both mRNA bands (7.5 and 9.0 kb) approximately 2-fold, whereas IL-6 stimulated mainly the upper 9.0 kb mRNA band. Cysteine proteinase inhibitor (CPI), mRNA and protein levels were elevated by combinations of cytokines; however, IL-1 seemed to inhibit the IL-6+Dex mediated stimulation of CPI mRNA, possibly through inhibition of IL-6R expression and induction of a soluble form of the receptor. This study showed that both IL-1 and OSM are involved in the regulation of the IL-6 receptor complex, and that different combinations of cytokines can affect the complexity and magnitude of the hepatic acute phase response.
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IL-6 and related cytokines as the critical lynchpins between inflammation and cancer
2014, Seminars in ImmunologyCitation Excerpt :IL-11Rα has been found on hepatocytes, gastrointestinal epithelial cells, T cells, B cells, macrophages, cardiac myocytes, fibroblasts, endothelial cells, osteoclasts and osteoblasts [15,146]. Expression of IL-6Rα is regulated by IL-6, OSM, IL-1, and dexamethasone [148,149] but it is not clear how the expression of IL-11Rα is regulated [13]. gp130 expression is ubiquitous [15] and is reported to be regulated by STAT3, STAT1 and ERK2 [150–152].
Inflammatory responses play pivotal roles in cancer development, including tumor initiation, promotion, progression, and metastasis. Cytokines are now recognized as important mediators linking inflammation and cancer, and are therefore potential therapeutic and preventive targets as well as prognostic factors. The interleukin (IL)-6 family of cytokines, especially IL-6 and IL-11, is highly up-regulated in many cancers and considered as one of the most important cytokine families during tumorigenesis and metastasis. This review discusses molecular mechanisms linking the IL-6 cytokine family to solid malignancies and their treatment.
Soluble interleukin-6 receptor enhanced by oncostatin M induces major changes in gene expression profile of human hepatoma cells
2002, Immunology LettersInterleukin-6 (IL-6) binds to a receptor complex consisting of an 80 kDa binding unit (IL-6R) and gp130 responsible for signal transduction. Due to alternative splicing and/or proteolytic digestion IL-6R occurs in soluble form (sIL-6R), as well. Soluble IL-6R is able to bind to gp130 expressing on nucleated cells, thus sIL-6R makes most cells responsive to IL-6. In this study we found that oncostatin M (OSM), an other gp130 dependent cytokine with proliferation inhibitory potential, increases the expression of both membrane-bound IL-6R and sIL-6R generated by alternative splicing in hepatic and mammary carcinoma cell lines. Furthermore, we studied the functional relevance of the presence and binding of soluble IL-6R to HepG2 cells. Using a cDNA expression array, mRNA levels of about 580 human genes were tested by differential display analysis. Our findings suggest, that elevation of surface density of IL-6R by attachment of sIL-6R induces major modulation in gene expression profile of the hepatoma cells. Soluble IL-6R alone has minor effect, it rather decreases expression of some genes, while incubation with IL-6 and sIL-6R together induces major changes in the mRNA pattern of HepG2 cells. These data strongly suggest that presence and binding of soluble cytokine receptors are important elements of inter-cytokine cross talk and affects actual gene expression profile of responding cells.
The role of oncostatin M in bone metabolism is not clearly defined, and the actions of mouse oncostatin M (mOSM) on osteoclast development has not been previously determined. We therefore examined the ability of recombinant mOSM to stimulate osteoclast formation and activity using cocultures of murine calvaria and bone marrow cells, and compared the responses to other members of the interleukin 6 family of cytokines including mouse leukaemia inhibitory factor (LIF), cardiotrophin-1 (CT-1) and IL-6. Mouse OSM, LIF and CT-1 strongly induced the formation of tartrate resistant acid phosphatase positive (TRAP+) multinucleated cells (MNC) in a dose-dependent fashion. OSM, LIF or CT-1 also elevated the number and size of resorptive pits when cocultures were added to smooth cortical bone slices, indicating enhancement of osteoclast activity. The activity of OSM was reduced by indomethacin (10−8–10−6 M), whereas addition of dexamethasone (DEX) at 10−7–10−5 M synergistically enhanced OSM-induced numbers of TRAP+MNC. DEX (10−7 M) costimulation also synergistically enhanced TRAP+cell numbers of LIF, and CT-1 treated cocultures. IL-6 had no activity alone, but further enhanced TRAP+cell formation in mOSM or DEX (10−7 M) treated cocultures. When added to mouse calvarial osteoblast cultures, mOSM induced secretion of IL-6 protein and elevation of mRNA whereas LIF or CT-1 did not. IL-6 mRNA levels and protein secretion were reduced in osteoblasts by costimulation with DEX. These results show that mouse OSM, LIF and CT-1 induce osteoclast differentiation and activation, that DEX synergizes with each in this activity, and that mouse OSM induces responses in osteoblasts that are not shown by LIF or CT-1. Collectively these data suggest an important role of these cytokines in osteoporosis caused by high levels of corticosteroid.
Factors influencing the effect of the soluble IL-6 receptor on IL-6 responses in HepG2 hepatocytes
2000, CytokineThe soluble IL-6 receptor (sIL-6R) can increase IL-6-induced signalling by forming a complex with IL-6 and membrane-bound gp130 (the receptor beta chain which transduces signals). The conditions affecting this response to sIL-6R were studied using fibrinogen release from HepG2 hepatocytes. Exogenous sIL-6R had no effect alone or in the presence of a submaximal concentration of IL-6, but increased responses to supramaximal IL-6 concentrations in a concentration-related manner. Dexamethasone increased the expression of the membrane IL-6R and endogenous sIL6R release, and increased responses to supramaximal but not submaximal IL-6 concentrations. The amount of endogenous sIL-6R released is relatively small and is unlikely to influence the effects of the exogenous sIL-6R. The observed concentration-related decrease in sIL-6R production in the presence of IL-6 may indicate internalization of ligand/receptor complexes. This would significantly decrease the amount of IL-6R (soluble or membrane) available for signalling and limit continued functional response later in the cultures. These data indicate that the major factor influencing responses to exogenous sIL-6R is an excess of IL-6 which is necessary to form complexes with the sIL-6R, which can then interact with gp130 to increase signalling.
Interleukin-6 expression and regulation in astrocytes
1999, Journal of NeuroimmunologyThe physiological function of interleukin-6 (IL-6) within the central nervous system (CNS) is complex; IL-6 exerts neurotrophic and neuroprotective effects, and yet can also function as a mediator of inflammation, demyelination, and astrogliosis, depending on the cellular context. In the normal brain, IL-6 levels remain low. However, elevated expression occurs in injury, infection, stroke, and inflammation. Given the diverse biological functions of IL-6 and its expression in numerous CNS conditions, it is critical to understand its regulation in the brain in order to control its expression and ultimately its effects. Accumulating data demonstrate that the predominant CNS source of IL-6 is the activated astrocyte. Furthermore, a wide range of factors have been demonstrated to be involved in IL-6 regulation by astrocytes. In this review, we summarize information concerning IL-6 regulation in astrocytes, focusing on the role of proinflammatory factors, neurotransmitters, and second messengers.
Cytokine network in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy
1999, American Journal of CardiologyInflammatory cytokines may play a pathogenic role in the development of congestive heart failure (CHF). Elevated circulating levels of inflammatory cytokines have been reported in CHF, but most studies have focused on only a few cytokine parameters. However, the activity of these cytokines are modulated by soluble cytokine receptors and cytokines with anti-inflammatory activities, and in the present study several of these interacting factors were examined simultaneously in 38 CHF patients with various degrees of heart failure and in 21 healthy controls. Patients with CHF had increased plasma concentrations of tumor necrosis factor (TNF)α, interleukin-6, soluble TNF receptors and the soluble interleukin-6 receptor, glycoprotein (gp)130. They also had elevated ratios of TNFα/soluble TNF receptors and interleukin-6/soluble gp130 as well as enhanced interleukin-6 bioactivity in serum, suggesting inflammatory net effects. In addition to raised circulating levels of inflammatory cytokines, CHF patients with severe heart failure also had abnormalities in the levels of anti-inflammatory cytokines, with decreased levels of transforming growth factor β1 and inadequately raised interleukin-10 in relation to the elevated TNFα concentrations. This dysbalance between inflammatory and anti-inflammatory cytokines was also found in monocyte supernatants from CHF patients. The abnormalities in the cytokine network were most pronounced in patients with the most severe heart failure, and several of the immunologic parameters, in particular soluble gp130, were correlated with variables reflecting deranged hemodynamic status. The present study analyzing the complexity of the cytokine network in CHF, demonstrates profound disturbances in the levels of both inflammatory and anti-inflammatory mediators with a marked dysbalance favoring inflammatory effects.