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Results for “Interleukin-18 Receptor alpha Subunit”

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At least 19 recordsLinked to original sources
PubMed1998

Constitutive and induced IL-18 receptor expression by various peripheral blood cell subsets as determined by anti-hIL-18R monoclonal antibody.

Interleukin-18 (IL-18) was identified as a molecule that induces IFN-gamma production and enhances NK cell cytotoxicity. Characterization of the receptor for human IL-18 (hIL-18R) is important for investigating the physiological role of IL-18 in nature. In the present study, we describe a monoclonal antibody (mAb) against hIL-18R (mAb No. 117-10C). This mAb inhibited the binding of 125I-labeled hIL-18 to IL-18R-expressing L428 cells. This mAb also neutralized hIL-18-induced T helper 1 type cytokine (IFN-gamma and GM-CSF) production by Con A-stimulated PBMC. PBMC were examined for the expression of IL-18R by two-color flow cytometry. Most CD19(+) B cells and a percentage of CD8(+) T cells were found to constitutively express IL-18R. Treatment of PBMC with IL-12 preferentially induced IL-18R expression on CD56(+) NK cells regardless of costimulation with mitogen. IL-18R expression on CD4(+) T cells was induced weakly by IL-12 treatment and moderately by PHA stimulation. However, neither could IL-12 treatment nor PHA stimulation induce IL-18R expression on CD8(+) T cells. Costimulation with both IL-12 and PHA was necessary for optimal IL-18R expression on CD8(+) T cells as well as on CD56(+) NK cells, CD4(+) T cells, and CD19(+) B cells. These results support the growing number of reports showing that IL-18 has modulatory effects on T, B, and NK cells.

Animals↗
PubMedDate not supplied

Simultaneous exposure to interleukin-18 and interleukin-10 in vitro synergistically augments murine spleen natural killer cell activity.

Interleukin-18 (IL-18) enhances interferon gamma (IFNgamma) production and natural killer (NK) cell activity, and elicits protective antitumor effects in vivo. IL-18 and IL-12 synergistically augment IFNgamma production reportedly because IL-12 enhances IL-18 receptor (IL-18R) expression. We now show that IL-18 also synergizes with IL-10 to augment murine splenic NK activity against Yac-1 cells in a standard 4-h chromium-release assay, but IFNgamma production is only slightly enhanced. This pattern of NK activity was also observed with severe combined immunodeficient (SCID) mouse spleen cells indicating that the cytokines were not acting on T or B cells. The cytokines had no priming activity on the spleen cells and, when cells were left unstimulated for 24 h in culture, little NK activity was induced when IL-18 was added for the next 24 h. The reverse transcriptase/polymerase chain reaction revealed that IL-18 receptor (IL-18R) mRNA was expressed early during in vitro spleen cell culture but none was expressed after culture for 24 h regardless of the stimulus. Binding of 125I-labeled IL-18 revealed that exposure to IL-10 only slightly increased IL-18R expression. Expression of perforin mRNA was constitutive and was unaffected by the cytokines; however, Fas ligand (FasL) mRNA expression was strong in cultures with IL-18 alone or combined with IL-10. When Fas-expressing cells and their parental cells were used as targets, weak Fas-mediated cytolytic activity was observed after exposure to IL-18, and this was further enhanced by combination with IL-10. Finally, the augmentation of NK activity was abrogated by the inhibitor concanamycin A, indicating that the enhanced NK activity is perforin-dependent.

Animals↗
PubMed1998

Establishment of the cells useful for murine interleukin-18 bioassay by introducing murine interleukin-18 receptor cDNA into human myelomonocytic KG-1 cells.

We genetically engineered human myelomonocytic KG-I cells by introducing cDNA of murine interleukin-18 receptor (MuIL-18R) and established human cells which were capable of responding to MuIL-18. These cells expressed larger number of MuIL-18R (> 13,000 sites/cell) than intrinsic human IL-18 receptor (HuIL-18R) (< 2,500 sites/cell). And the cells responded to MuIL-18 as well as to HuIL-18 in a dose-dependent manner, and produced large amounts of interferon-gamma (IFN-gamma). We could estimate the amount of murine IL-18 based on the amounts of IFN-gamma produced by these cells. The stoichiometry was observed up to 150 ng/ml of MuIL-18. By using these cells, a large amount of MuIL-18 (448 +/- 89.2 ng/ml) was detected in sera of Propionibacterium acnes (P. acnes)/lipopolysaccharide (LPS)-treated endotoxic mice (the same conditions in which IL-18 was first identified). These cells provide us with a useful tool for determining the bioactivity of MuIL-18.

Animals↗
PubMed1996

Cloning of a cDNA encoding a novel interleukin-1 receptor related protein (IL 1R-rp2).

We have identified and isolated both the rat and human cDNAs for a novel putative receptor related to the interleukin-1 type 1 receptor. We have named this protein interleukin 1 receptor related protein two (IL 1R-rp2). The rat cDNA for IL1R-rp2 was first identified using oligonucleotides of degenerate sequence in a polymerase chain reaction (PCR) paradigm with rat brain mRNA as the template. The protein encoded by both of these cDNAs are 561 amino acids long and exhibit 42% and 26% overall identity with the interleukin-1 type 1 and type 2 receptors, respectively. RNase protection assays from rat tissues revealed a predominant expression for IL 1R-rp2 in the lung and epididymis with lower levels detected in the testis and cerebral cortex. By in situ hybridization we were able to determine that the expression in rat brain appeared to be non-neuronal and associated with the cerebral vasculature. When expressed transiently in COS-7 cells the receptor was incapable of high affinity binding to either [125I]-recombinant human IL 1 alpha or [125I]-recombinant human IL 1 beta. Together, these data demonstrate the existence of a novel protein that is related to the interleukin-1 receptor but does not bind IL-1 by itself.

Amino Acid Sequence↗
PubMed1998

Regulation of interferon-gamma production by IL-12 and IL-18.

IL-18 (interferon-inducing factor) and IL-12 exhibit a marked synergism in interferon-gamma induction in T cells. Investigations into the mechanism of this synergism have revealed that IL-12 upregulates expression of the IL-18 receptor on cells producing interferon-gamma. Although IL-18 does not induce the development of Th1 cells, it is essential for the effective induction and activation of Th1 cells by IL-12. As for natural killer cells, IL-18 seems to activate them independently of IL-12. Although IL-12 and IL-18 activate both innate and acquired immunity, their excessive production by activated macrophages may induce multiple organ disorders including disruption of the immune system.

Animals↗
PubMed1998

Interleukin-18: perspectives on the newest interleukin.

Just over two years ago the newest member of the interleukin family of cytokines, IL-18, was molecularly cloned. IL-18 was originally identified as a result of its ability to induce interferon gamma production, however with the advent of its cloning and the production of recombinant protein a number of other biological actions have since been identified. Recently the receptor for IL-18 was also characterised. Due to the structural and biological properties shared between IL-18 and IL-1 and their respective receptors, questions relating to IL-18 activities are being answered at a rapid pace. This article addresses the biology of IL-18 in both disease and non-disease states.

Amino Acid Sequence↗
PubMed1999

Different promoter usage and multiple transcription initiation sites of the interleukin-1 receptor-related human ST2 gene in UT-7 and TM12 cells.

The ST2 gene encodes receptor-like molecules that are very similar to the type I interleukin-1 receptor. Two distinct types of the ST2 gene products, ST2 (a soluble secreted form) and ST2L (a transmembrane form) are produced by alternative splicing. Here we demonstrate that the human ST2 gene has two alternative promoters followed by distinct noncoding first exons, which are located more than 8 kb apart and are spliced to the common exon 2 containing the translation initiation site. Within 1001 bp upstream of the transcription initiation site of the cloned distal promoter, there are four GATA-1. The main promoter used for the expression of the ST2 gene in UT-7, a human leukaemic cell line, is distinct from that in TM12, a human fibroblastic cell line. Although UT-7 cells use both distal and proximal promoters, the distal promoter is used dominantly for expression of both ST2 and ST2L mRNA. On the other hand, almost all transcription in TM12 cells starts from the proximal promoter. These results contrast with those of former studies on the rat system, in which ST2 and ST2L mRNA were generated by use of the proximal and distal promoters, respectively. Furthermore, UT-7 cells use multiple transcription initiation sites in both the proximal and distal promoters, whereas the transcription of the ST2 gene in TM12 cells starts at a unique site. Intriguingly, these results suggest that ST2 and ST2L proteins have distinct functions in different cells within different biological systems, such as those of growth control, differentiation and immunological responses.

Alternative Splicing↗
PubMed1996

IL-1Rrp is a novel receptor-like molecule similar to the type I interleukin-1 receptor and its homologues T1/ST2 and IL-1R AcP.

A novel member of the interleukin-1 receptor family has been cloned by polymerase chain reaction using degenerate oligonucleotide primers derived from regions of sequence conservation, using as template a yeast artificial chromosome known to contain both interleukin-1 (IL-1) receptors and T1/ST2. The new receptor, called IL-1 receptor-related protein or IL-1Rrp, fails to bind any of the known IL-1 ligands. A chimeric receptor, in which the IL-1Rrp cytoplasmic domain is fused to the extracellular and transmembrane regions of the IL-1 receptor, responds to IL-1 following transfection into COS cells by activation of NFkappaB and induction of IL-8 promoter function.

Amino Acid Sequence↗
PubMed1997

Purification and characterization of the human interleukin-18 receptor.

Interleukin (IL)-18 was identified as a molecule that induces IFN-gamma production and enhances NK cell cytotoxicity. In this paper, we report upon the purification and characterization of human IL-18 receptor (hIL-18R). We selected the Hodgkin's disease cell line, L428, as the most strongly hIL-18R-expressing cell line based on the results of binding assays. This binding was inhibited by IL-18 but not by IL-1beta. The dissociation constant (Kd) of 125I-IL-18 binding to L428 cells was about 18.5 nM, with 18,000 binding sites/cell. After immunizing mice with L428 cells and cloning, a single monoclonal antibody (mAb) against hIL-18R was obtained (mAb 117-10C). Sequentially, hIL-18R was purified from 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid (CHAPS)-extracted L428 cells by wheat germ lectin-Sepharose 4B chromatography and mAb 117-10C-Sepharose chromatography. The internal amino acid sequences of hIL-18R all matched those of human IL-1 receptor-related protein (IL-1Rrp), the ligand of which was unknown to date. When expressed in COS-1 cells, the cDNA of IL-1Rrp conferred IL-18 binding properties on the cells and the capacity for signal transduction. From these results, we conclude that a functional IL-18 receptor component is IL-1Rrp.

Amino Acid Sequence↗
PubMed1998

Selective expression and functions of interleukin 18 receptor on T helper (Th) type 1 but not Th2 cells.

Interleukin (IL)-18 induces interferon (IFN)-gamma synthesis and synergizes with IL-12 in T helper type 1 (Th1) but not Th2 cell development. We report here that IL-18 receptor (IL-18R) is selectively expressed on murine Th1 but not Th2 cells. IL-18R mRNA was expressed constitutively and consistently in long-term cultured clones, as well as on newly polarized Th1 but not Th2 cells. IL-18 sustained the expression of IL-12Rbeta2 mRNA, indicating that IL-18R transmits signals that maintain Th1 development through the IL-12R complex. In turn, IL-12 upregulated IL-18R mRNA. Antibody against an IL-18R-derived peptide bound Th1 but not Th2 clones. It also labeled polarized Th1 but not Th2 cells derived from naive ovalbumin-T cell antigen receptor-alphabeta transgenic mice (D011.10). Anti-IL-18R antibody inhibited IL-18- induced IFN-gamma production by Th1 clones in vitro. In vivo, anti-IL-18R antibody reduced local inflammation and lipopolysaccharide-induced mortality in mice. This was accompanied by shifting the balance from Th1 to Th2 responses, manifest as decreased IFN-gamma and proinflammatory cytokine production and increased IL-4 and IL-5 synthesis. Therefore, these data provide a direct mechanism for the selective effect of IL-18 on Th1 but not Th2 cells. They also show that the synergistic effect of IL-12 and IL-18 on Th1 development may be due to the reciprocal upregulation of their receptors. Furthermore, IL-18R is a cell surface marker distinguishing Th1 from Th2 cells and may be a therapeutic target.

Animals↗
PubMed1999

Defective interleukin (IL)-18-mediated natural killer and T helper cell type 1 responses in IL-1 receptor-associated kinase (IRAK)-deficient mice.

Interleukin (IL)-18 is functionally similar to IL-12 in mediating T helper cell type 1 (Th1) response and natural killer (NK) cell activity but is related to IL-1 in protein structure and signaling, including recruitment of IL-1 receptor-associated kinase (IRAK) to the receptor and activation of c-Jun NH2-terminal kinase (JNK) and nuclear factor (NF)-kappaB. The role of IRAK in IL-18-induced responses was studied in IRAK-deficient mice. Significant defects in JNK induction and partial impairment in NF-kappaB activation were found in IRAK-deficient Th1 cells, resulting in a dramatic decrease in interferon (IFN)-gamma mRNA expression. In vivo Th1 response to Propionibacterium acnes and lipopolysaccharide in IFN-gamma production and induction of NK cytotoxicity by IL-18 were severely impaired in IRAK-deficient mice. IFN-gamma production by activated NK cells in an acute murine cytomegalovirus infection was significantly reduced despite normal induction of NK cytotoxicity. These results demonstrate that IRAK plays an important role in IL-18-induced signaling and function.

Animals↗
PubMed1998

Cloning and expression of a single-chain Fv fragment specific for the human interleukin 18 receptor.

We have recently reported the successful purification and characterization of the human interleukin 18 (IL-18) receptor (R) using a monoclonal antibody (MAb) of the IgM kappa class (117-10C) after immunizing mice with cells of the Hodgkin's disease-derived cell line L428. This antibody is specific for the human IL-18R and inhibits the bioactivity of IL-18. Here we report on the polymerase chain reaction (PCR)-assisted cloning and sequencing of cDNAs encoding the variable regions of the light and heavy chains of 117-10C. We expressed the antibody in the form of a single-chain Fv fragment (scFv) in Chinese Hamster Ovary (CHO) cells and purified it from culture supernatants by chromatography. The purified scFv has an affinity for IL-18R of 5.6 x 10(8) M(-1), whereas 117-10C binds to the receptor with an affinity constant of 3.6 x 10(9) M(-1). Since 117-10C is of the IgM class, it is expected to be in the pentamer form and should theoretically therefore bind IL-18R with 10 times the affinity of the single-chain fragment may explain the difference in the affinity constants for the two molecules. The inhibitory efficiency of 117-10C was found to be 6-fold that of scFv in an interferon gamma (IFN-gamma)-inducing assay on the IL-18-responsive cell line KG-1. In conclusion, we have produced a single-chain fragment of a murine anti-human IL-18R antibody that is as potent at binding IL-18 as the parent antibody, and may be useful in neutralizing the cytokine in human conditions associated with high production of IL-18.

Amino Acid Sequence↗
PubMed1999

Neuroblastoma cells expressing mature IL-18, but not proIL-18, induce a strong and immediate antitumor immune response.

Retroviral constructs were designed to express the novel cytokine interleukin 18 (IL-18), also known as interferon-gamma-inducing factor, in a murine neuroblastoma cell line [neuro-2a (N-2a)] to examine the effects of IL-18 expression on tumorigenicity. N-2a cells expressing proIL-18 (N-2a/IL-18p) were as tumorigenic as parental N-2a cells, whereas N-2a cells engineered to secrete mature IL-18 (N-2a/IL-18m) were nontumorigenic. Inoculation of mice with N-2a/IL-18m generated immediate immunity to parental N-2a. N-2a/IL-18m formed tumors in mice depleted of CD4+ and CD8+ T cells, suggesting that the antitumor immune response was T cell mediated. The resulting T-helper (Th) immune response was also characterized in vitro and had a large Th1 component based on in vitro production of the cytokines IFN-gamma and granulocyte macrophage colony-stimulating factor in response to tumor cells and IL-18.

Animals↗
PubMed1999

Differential cytokine and chemokine gene expression by human NK cells following activation with IL-18 or IL-15 in combination with IL-12: implications for the innate immune response.

NK cells constitutively express monocyte-derived cytokine (monokine) receptors and secrete cytokines and chemokines following monokine stimulation, and are therefore a critical component of the innate immune response to infection. Here we compared the effects of three monokines (IL-18, IL-15, and IL-12) on human NK cell cytokine and chemokine production. IL-18, IL-15, or IL-12 alone did not stimulate significant cytokine or chemokine production in resting NK cells. The combination of IL-18 and IL-12 induced extremely high amounts of IFN-gamma protein (225 +/- 52 ng/ml) and a 1393 +/- 643-fold increase in IFN-gamma gene expression over those in resting NK cells. IL-15 and IL-12 induced less IFN-gamma protein (24 +/- 10 ng/ml; p < 0.007) and only a 45 +/- 19-fold increase in IFN-gamma gene expression over those in resting NK cells. The CD56bright NK cell subset produced significantly more IFN-gamma following IL-18 and IL-12 compared with CD56dim NK cells (p < 0.008). However, the combination of IL-15 and IL-12 was significantly more potent than that of IL-18 and IL-12 for NK cell production of IL-10, macrophage inflammatory protein-1alpha, macrophage inflammatory protein-1beta, and TNF-alpha at the protein and transcript levels. Granulocyte-macrophage CSF was optimally induced by IL-15 and IL-18. Resting CD56+ NK cells expressed IL-18R transcript that was up-regulated by IL-12 or IL-15. Our results show that distinct cytokine and chemokine patterns are induced in NK cells in response to different costimulatory signals from these three monokines. This suggests that NK cell cytokine production may be governed in part by the monokine milieu induced during the early proinflammatory response to infection and by the subset of NK cells present at the site of inflammation.

CD56 Antigen↗
PubMed1999

Cutting edge: generation of IL-18 receptor-deficient mice: evidence for IL-1 receptor-related protein as an essential IL-18 binding receptor.

IL-18 is a proinflammatory cytokine that plays an important role in NK cell activation and Th1 cell response. Recently IL-1R-related protein (IL-1Rrp) has been cloned as the receptor for IL-18. However, the functional role of IL-1Rrp is still controversial due to its low affinity to IL-18 as well as the possibility of the presence of another high-affinity binding receptor. In the present study, we have generated and characterized IL-1Rrp-deficient mice. The binding of murine rIL-18 was not detected in Th1-developing splenic CD4+ T cells isolated from IL-1Rrp-deficient mice. The activation of NF-kappa B or c-Jun N-terminal kinase were also not observed in the Th1 cells. NK cells from IL-1Rrp-deficient mice had defects in cytolytic activity and IFN-gamma production in response to IL-18. Th1 cell development was also impaired in IL-1Rrp-deficient mice. These data demonstrate that IL-1Rrp is a ligand-binding receptor that is essential for IL-18-mediated signaling events.

Animals↗
PubMed1998

Differential capacities of CD4+, CD8+, and CD4-CD8- T cell subsets to express IL-18 receptor and produce IFN-gamma in response to IL-18.

IL-12 and IL-18 have the capacity to stimulate IFN-gamma production by T cells. Using a T cell clone, we reported that IL-18 responsiveness is generated only after exposure to IL-12. Here, we investigated the induction of IL-18 responsiveness in resting CD8+, CD4+, and CD4-CD8- T cells. Resting T cells respond to neither IL-12 nor IL-18. After stimulation with anti-CD3 plus anti-CD28 mAbs, CD8+, CD4+, and CD4-CD8- T cells expressed IL-12R, but not IL-18R, and produced IFN-gamma in response to IL-12. Cultures of T cells with anti-CD3/anti-CD28 in the presence of rIL-12 induced IL-18R expression and IL-18-stimulated IFN-gamma production, which reached higher levels than that induced by IL-12 stimulation. However, there was a substantial difference in the expression of IL-18R and IL-18-stimulated IFN-gamma production among T cell subsets. CD4+ cells expressed marginal levels of IL-18R and produced small amounts of IFN-gamma, whereas CD8+ cells expressed higher levels of IL-18R and produced more IFN-gamma than CD4+ cells. Moreover, CD4-CD8- cells expressed levels of IL-18R comparable to those for CD8+ cells but produced IFN-gamma one order higher than did CD8+ cells. These results indicate that the induction of IL-18R and IL-18 responsiveness by IL-12 represents a mechanism underlying enhanced IFN-gamma production by resting T cells, but the operation of this mechanism differs depending on the T cell subset stimulated.

Animals↗
PubMed1998

[IL-18 and IL-18 receptor].

Interleukin-18 (IL-18) is a recently cloned cytokine, produced from activated macrophages, including Kupffer cells. IL-18 is originally called interferon-gamma inducing factor (IGIF), due to its action to induce IFN-gamma production from Th 1 cells and NK cells. However, recent studies suggested that, IL-18 also enhances expression of FasL and NK activity as well as GM-CSF production. These data revealed this novel cytokine is pleiotropic. Recently, cDNA encoding human IL-18 receptor (IL-18R) was cloned. And, we had cloned murine IL-18R cDNA by RT-PCR, using human IL-18R sequence. Northern blot analysis of cytoplasmic RNA from T cells stimulated with IL-12 clearly demonstrated that, T cells stimulated with IL-12 induced high level of IL-18R-mRNA, whereas non-stimulated T cells did not have. Interestingly, we had several reports, indicated the involvement of IL-18 on the progressions of pathogenicity in chronic inflammatory diseases, including endotoxin-shock, hepatitis and autoimmune-diabetes. We need further studies to reveal physiological roles of this novel cytokine in various inflammatory or autoimmune diseases.

Animals↗