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IL-18 Receptor (il-18 + receptor)

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Medical Sciences	88%

Selected Abstracts

Bovine Anterior Pituitary Progenitor Cell Line Expresses Interleukin (IL)-18 and IL-18 Receptor

JOURNAL OF NEUROENDOCRINOLOGY, Issue 11 2008
Y. Nagai
In the anterior pituitary gland, inflammatory mediators regulate cell function through an immuno-endocrine pathway. Recent studies have shown that undifferentiated stem cells act as immunomodulators. These studies prompted us to establish a progenitor cell line from the bovine anterior pituitary gland and to detail its function. First, we localised interleukin (IL)-18 by immunohistochemistry to the marginal cell layer of Rathke's pouch that is assumed to embody a stem/progenitor cell compartment of the postnatal pituitary gland. A cloned anterior pituitary-derived cell line from the bovine anterior pituitary gland was established from single cell clone by the limiting dilution method and was designated as bovine anterior pituitary-derived cell line (BAPC)-1. BAPC-1 cells constantly expressed mRNAs for IL-18 and IL-18 receptor, and grew steadily and rapidly in the medium containing epidermal growth factor and basic fibroblast growth factor. The cell line also expressed the mRNAs for the stem/progenitor cell- related factors such as Nanog, Oct-4, Ptch1, Nestin, Notch1, Hes1, Lrp and Fzd4, and the mRNAs for embryonic pituitary-related factors, such as Lhx3, PitX1 and Pit-1. The nuclei of BAPC-1 were immunostained positively for Pit-1, Hes1 and ,-catenin antibodies. Furthermore, BAPC-1 cells expressed mRNAs for cytokine such as IL-1,, IL-6, IL-7, IL-12 and IL-15. Stimulation of BAPC-1 cells with IL-18 increased expression of mRNAs for IL-1,, IL-6, IL-1, and IL-8. At day 6 in culture, BAPC-1 cells also express growth hormone mRNA. These results strongly suggest that BAPC-1 is a stem/progenitor cell line and modulates the immuno-endocrine function of the anterior pituitary cells through its cytokine production. [source]

Role of interleukin-18 and its receptor in hepatocellular carcinoma associated with hepatitis C virus infection

INTERNATIONAL JOURNAL OF CANCER, Issue 3 2006
Masami Asakawa
Abstract Interleukin (IL)-18 is a proinflammatory cytokine that is up-regulated in patients with hepatitis C virus (HCV) infection, which is the most common underlying disease in hepatocellular carcinoma (HCC). The purpose of our study was to investigate the role of IL-18 in HCC associated with HCV infection. Sixty-five patients with HCC and HCV infections who received curative surgical resections were examined in our study. The expression of the IL-18 receptor was investigated in HCC tissues obtained from these patients and in 2 HCC cell lines. Nuclear factor (NF)-,B activity and the expression of Bcl-xL and xIAP mRNA were tested in the cell lines using recombinant human (rh) IL-18. The IL-18 receptor was expressed in both the HCC tissues and the cell lines. NF-,B activation and the expression of Bcl-xL and xIAP mRNA were increased by rhIL-18. Moreover, rhIL-18 suppressed the apoptosis of HCC cells which was induced by etoposide in vitro. The overall survival rate (55.4%) was significantly worse in the IL-18 receptor-positive patients than in the IL-18 receptor-negative patients (p = 0.015). In a Cox multivariate analysis, the expression of the IL-18 receptor was found to be a significant predictor of a poor outcome in HCC patients. The expression of the IL-18 receptor and an antiapoptotic mechanism involving NF-,B activation in HCC cells may be implicated in a poor patient outcome. © 2005 Wiley-Liss, Inc. [source]

Bovine Anterior Pituitary Progenitor Cell Line Expresses Interleukin (IL)-18 and IL-18 Receptor

Effects of interleukin 18 on injury and activation of human proximal tubular epithelial cells

NEPHROLOGY, Issue 1 2007
DONG LIANG
SUMMARY: Background/Aims: Injury and activation of tubular proximal epithelial cells (TEC) play central roles in renal tubulointerstitial fibrosis (TIF), but its mechanisms remain obscure. Interleukin 18 (IL-18) is overproduced during chronic kidney diseases (CKD), but how IL-18 affects the biological behaviour of TEC is not clear. The aim of the present study is to reveal the role of IL-18 in renal TIF. Methods: The expressions of IL-18 and IL-18 receptor in TEC were detected by immunohistochemical staining in vivo and by reverse transcriptase polymerase chain reaction (RT-PCR) in vitro. TEC line (HK-2 cells) were incubated without or with IL-18. Cell proliferation and cell cycle were evaluated by methyl thiazolyl tetrazolium assay and flow cytometric analysis, respectively. Cell apoptosis was assessed by Hoechst 33258 staining. Expression of ,-smooth muscle actin was evaluated by RT-PCR, immunocytochemical staining and flow cytometric analysis, respectively. Type I collagen, fibronectin, MCP-1 and RANTES in cultured supernatants were measured by enzyme-linked immunosorbent assay. Results: IL-18 expression in TEC increased significantly in CKD state. IL-18 receptor was constitutively expressed in normal proximal TEC, and its expression increased strongly in CKD state. Proliferation and cell cycle of HK-2 cells were not affected by IL-18. Cell apoptosis, ,-smooth muscle actin expression, type I collagen and fibronectin production as well as MCP-1 secretion were promoted by IL-18 in dosage- and/or time-dependent manners, but RANTES secretion was not affected. Conclusion: IL-18 may play a crucial role in the process of TIF by promoting TEC injury and activation, and could be a target of the therapeutic approaches against TIF. [source]

Defective phosphorylation of interleukin-18 receptor , causes impaired natural killer cell function in systemic-onset juvenile idiopathic arthritis

ARTHRITIS & RHEUMATISM, Issue 9 2009
Wilco de Jager
Objective Systemic-onset juvenile idiopathic arthritis (JIA) is an autoimmune disease characterized by arthritis and systemic features. Its pathogenesis is still largely unknown. It is characterized immunologically by natural killer (NK) cell dysfunction and cytokine signatures that predominantly feature interleukin-1 (IL-1), IL-6, and IL-18. Since IL-18 can drive NK cell function, we examined how the high plasma levels of this cytokine are related to the documented NK cell failure in these patients. Methods The phenotype and function of NK cells from 10 healthy control subjects, 15 patients with polyarticular JIA, and 15 patients with systemic-onset JIA were characterized by staining and functional assays in vitro. IL-18 ligand binding was visualized by fluorescence microscopy. Phosphorylation of several MAP kinases and the IL-18 receptor , (IL-18R,) were visualized by Western blotting. Results IL-18 from the plasma of systemic-onset JIA patients stimulated the activation of NK cells from healthy controls and bound its cognate receptor. However, NK cells from systemic-onset JIA patients failed to up-regulate cell-mediated killing molecules, such as perforin and interferon-,, after IL-18 stimulation. Furthermore, treatment with IL-18 did not induce the phosphorylation of receptor-activated MAP kinases in NK cells. Alternate activation of NK cells by IL-12 induced NK cell cytotoxicity. We observed no additive effect of IL-18 in combination with IL-12 in systemic-onset JIA patients. Immunoprecipitation of IL-18R, showed that NK cells from systemic-onset JIA could not phosphorylate this receptor after IL-18 stimulation. Conclusion The mechanism of the impaired NK cell function in systemic-onset JIA involves a defect in IL-18R, phosphorylation. This observation has major implications for the understanding and, ultimately, the treatment of systemic-onset JIA. [source]

Evidence for a pathogenetic role of interleukin-18 in cutaneous lupus erythematosus

ARTHRITIS & RHEUMATISM, Issue 10 2008
Dong Wang
Objective Cutaneous manifestations are the most common clinical features of lupus erythematosus (LE). The aim of this study was to analyze differences in the inflammatory response of keratinocytes from patients with cutaneous LE (CLE) compared with healthy controls. Methods Keratinocytes from LE patients and controls were cultured from epidermal stem cells of the hair follicle of anagen head hairs. Functional responses of keratinocytes to cytokine stimulation were determined by flow cytometry and enzyme-linked immunosorbent assay. Biopsy samples of lesional skin were analyzed by immunohistochemistry. Results Keratinocytes from CLE patients expressed higher levels of IL-18 receptor on their cell surface in response to tumor necrosis factor , (TNF,) or interferon-, stimulation. In response to IL-18 stimulation, these cells produced large amounts of TNF,. Of note, in the presence of IL-18, CLE keratinocytes failed to express IL-12. IL-12 has previously been shown to protect keratinocytes from ultraviolet irradiation,induced apoptosis. Keratinocytes from LE patients were more prone to die upon exposure to IL-18, and this increased apoptosis was abrogated by blockade of endogenously produced TNF, as well as by the addition of exogenous IL-12. IL-18 was highly expressed in biopsy samples of lesional skin from CLE patients. Conclusion Our results demonstrate an intrinsic difference in the inflammatory response of keratinocytes and indicate an autocrine feedback loop involving TNF,, IL-18, and IL-12 family members. Our results suggest that IL-18 may occupy an important position in the cytokine hierarchy in CLE, indicating the potential benefit of a local agent that blocks IL-18 activity in the treatment of the manifestations of CLE. [source]

Heterogeneity of response of rheumatoid synovium cell subsets to interleukin-18 in relation to differential interleukin-18 receptor expression

ARTHRITIS & RHEUMATISM, Issue 3 2003
Masanori Kawashima
Objective To examine the differential response of rheumatoid arthritis (RA) synovium cell subsets to interleukin-18 (IL-18), the effect of IL-18 on Th1-cytokine production, and the regulation of IL-18 by IL-18 binding protein (IL-18BP). Methods RA fibroblast-like synoviocytes were stimulated with IL-1,, IL-12, and IL-18, and levels of IL-6 were measured by enzyme-linked immunosorbent assay (ELISA). Expression of IL-18 receptor , and , chains (IL-18R, and IL-18R,, respectively), interferon-, (IFN,), and IL-17 messenger RNA (mRNA) by peripheral blood mononuclear cells, by total RA synovium cells containing T cells obtained after collagenase digestion, and by RA fibroblast-like synoviocytes was determined by reverse transcription,polymerase chain reaction. Levels of IFN, were measured by ELISA. Results IL-1, and, less effectively, IL-12 could induce RA fibroblast-like synoviocytes to produce IL-6, but IL-18 failed to have an effect. Although IL-18R, mRNA was constitutively expressed by RA fibroblast-like synoviocytes, IL-18R, could not be detected, either with or without stimulation with IL-1 or IL-12. Total RA synovium cells containing T cells showed a strong expression of both IL-18R, and IL-18R, mRNA, and only IL-18R, was up-regulated by IL-12. The combination of IL-12 and IL-18 synergistically up-regulated IFN, mRNA expression by total RA synovium cells containing T cells, but down-regulated that of IL-17. IL-12,induced IFN, production by total RA synovium cells containing T cells was increased by additional IL-18 and decreased by IL-18BP. Conclusion These results indicate that IL-18 plays an important role in RA inflammation and joint destruction via T cells and macrophages, but it does not have a direct effect on fibroblast-like synoviocytes. IL-18BP may be a tool for RA therapy because of its ability to neutralize endogenous IL-18. [source]

Multiple MyD88-dependent responses contribute to pulmonary clearance of Legionella pneumophila

CELLULAR MICROBIOLOGY, Issue 1 2009
Kristina A. Archer
Summary MyD88-dependent signalling is important for secretion of early inflammatory cytokines and host protection in response to Legionella pneumophila infection. Although toll-like receptor (TLR)2 contributes to MyD88-dependent clearance of L. pneumophila, TLR-independent functions of MyD88 could also be important. To determine why MyD88 is critical for host protection to L. pneumophila, the contribution of multiple TLRs and IL-18 receptor (IL-18R)-dependent interferon-gamma (IFN-,) production in a mouse was examined. Mice deficient for TLR5 or TLR9, or deficient for TLR2 along with either TLR5 or TLR9, were competent for controlling bacterial replication and had no apparent defects in cytokine production compared with control mice. MyD88-dependent production of IFN-, in the lung was mediated primarily by natural killer cells and required IL-18R signalling. Reducing IFN-, levels did not greatly affect the kinetics of L. pneumophila replication or clearance in infected mice. Additionally, IFN-,-deficient mice did not have a susceptibility phenotype as severe as the MyD88-deficient mice and were able to control a pulmonary infection by L. pneumophila. Thus, MyD88-dependent innate immune responses induced by L. pneumophila involve both TLR-dependent responses and IL-18R-dependent production of IFN-, by natural killer cells, and these MyD88-dependent pathways can function independently to provide host protection against an intracellular pathogen. [source]

IL-12 and IL-18 down-regulate B cell migration in an Ly49D-dependent manner

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2007
Gili Hart
Abstract In order to complete their maturation and participate in the humoral immune response, immature B cells that leave the bone marrow are targeted to specific areas in the spleen, where they differentiate into mature cells. Previously, we showed that immature B cells actively down-regulate their integrin-mediated migration to LN or to sites of inflammation, enabling their targeting to the spleen. This inhibition is mediated by IFN-,, which is transcribed and secreted at low levels by these immature B cells; its expression is subsequently down-regulated following B cell maturation. The activating and inhibitory MHC class,I receptors, Ly49D and Ly49G2, regulate IFN-, secretion in B cells, preventing their migration to antigen-enriched sites and their premature encounter with an antigen, while enabling their entry into the LN when mature. In the present study, we elucidate the pathways by which the Ly49 receptors regulate IFN-, levels. We show that Ly49D stimulation triggers a signaling cascade that increases transcription of both IL-12B and IL-18; these, in turn, can interact with their specific receptors, which are expressed at elevated levels on immature B cells. Ligation of the IL-12B and IL-18 receptors induces the secretion of IFN-,, thereby regulating their cytoskeleton rearrangement and migration. [source]