Recombinant Fc-IL-18BPc isoform inhibits IL-18-induced cytokine production.

Laboratory of Cytokine Immunology, Department of Biomedical Sciences and Technology, Konkuk University Medical Center, School of Medicine, Konkuk University, Seoul, Korea.
Hybridoma (2005) (Impact Factor: 0.33). 04/2012; 31(2):99-104. DOI: 10.1089/hyb.2011.0085
Source: PubMed

ABSTRACT IL-18 is a pro-inflammatory cytokine that is produced from T cells and NK cells. IL-18 has been implicated in the pathogenesis of various inflammatory and cardiovascular diseases. IL-18 binding protein (IL-18BP) is a natural inhibitor of IL-18 that possesses higher affinity to IL-18 than that of the IL-18 receptor alpha chain on the cell surface. Human isoform a and c among four isoforms of IL-18BPs have an inhibitory effect on IL-18-induced cytokines whereas mouse IL-18BP isoforms exist only in two isoforms: c and d. Fc-fusion protein is a molecule in which the immunoglobulin Fc is fused genetically to a protein of interest, such as an extracellular domain of a receptor, ligand, or enzyme. In this study, we expressed and purified human Fc-IL-18BPa and c isoforms from CHO-DG44 cells and their biological activities were compared to each other. This is the first time that expressed recombinant human Fc-IL-18BPc has been examined for its biological activity on IL-18-induced IFNγ in human PBMC and IL-6 in A549/IL-18Rβ.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The IL-18 binding protein (IL-18BP) is a circulating inhibitor of the proinflammatory cytokine IL-18. It is constitutively expressed in mononuclear cells, and elevated expression is induced by IFN-gamma. In this study, we characterized the IL-18BP promoter. We first showed that induction is at the transcriptional level and requires de novo protein synthesis. The IL-18BP promoter resides within 1.6 kb DNA upstream of the first exon and includes at least six regulatory elements. We identified in the basal promoter a gamma-activated sequence (GAS) proximal to the transcription start site (base 1), followed by an IFN regulatory factor 1 response element (IRF-E) and two CCAATenhancer binding protein beta (CEBPbeta) sites, all of which are essential for basal promoter activity. Furthermore, GAS and IRF-E were essential for IFN-gamma-induced transcription. Indeed, sera of IRF-1-deficient mice lacked basal and IFN-gamma-induced IL-18BP. We found that after induction of IRF-1 by IFN-gamma, it formed a complex with CEBPbeta, which bound to the IRF-E and GAS-containing proximal DNA. In contrast, the IFN-gamma-induced signal transducer and activator of transcription 1 dimer did not associate with this GAS. In addition, we identified a silencer element and a distal enhancer at bases -1081 to -1272, which was also physically associated with IRF-1. The IRF-1-CEBPbeta complex described here probably plays a fundamental role in regulating additional IFN-gamma-responsive genes.
    Proceedings of the National Academy of Sciences 01/2003; 99(26):16957-62. · 9.81 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Experimental autoimmune encephalomyelitis (EAE) is a model of autoimmune central nervous system (CNS) disease that is mediated by autoreactive Th1 cells secreting the proinflammatory cytokine interferon (IFN)-gamma. Interleukin (IL)-12 in its heterodimeric p35/p40 isoform and the recently described cytokine IL-18 potently induce T cell production of IFN-gamma. Interleukin-1beta converting enzyme (ICE) is required to convert IL-18 precursor protein into its biologically active mature form. In this study, we used semiquantitative reverse transciptase-polymerase chain reaction to determine steady state levels of IL-12, IL-18, and ICE mRNA in the spinal cord of Lewis rats at different stages of EAE. In control rats, we found significant IL-18, ICE, and IL-12p35, but not IL-12p40 mRNA expression. IL-18 mRNA increased during the acute stage of EAE together with a marked induction of ICE mRNA. IL-12p35 mRNA levels did not change significantly throughout the course of EAE. Surprisingly, the peak expression of IL-12p40 mRNA was delayed by several days relative to the peak of T cell infiltration and IFN-gamma mRNA synthesis. Our data implicate the IL-18/ICE pathway in the amplification of Th1-mediated immune responses in the CNS but suggest a different, so far undefined role of endogenous IL-12 in the late effector phase of EAE.
    Journal of Neuroimmunology 12/1998; 91(1-2):93-9. · 3.03 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: New treatment options for chronic hepatitis C (CHC) that offer improved efficacy, tolerability, and convenience compared with weekly interferon alfa (IFNalpha)-based regimens are needed. Longer-acting IFNalpha formulations with reduced dosing requirements and improved tolerability have been a focus of drug development efforts. The objective of this report is to review the characteristics, pharmacokinetics, pharmacodynamics, and clinical and virologic outcomes reported in studies of albinterferon alfa-2b (alb-IFN), a novel fusion protein of human albumin and human IFNalpha-2b. This review was based on all published data regarding alb-IFN to date. An unlimited PubMed database search was conducted using the keywords 'albuferon,' 'albinterferon,' and 'albumin AND interferon.' Albinterferon alfa-2b has been developed for the treatment of CHC. This agent exhibits a prolonged half-life and duration of antiviral activity that indicate potential suitability for dosing intervals of 2-4 weeks. Phase 2 trials in prior IFN nonresponders and IFN-naïve patients with genotype 1 or 2/3 CHC have shown antiviral activity and acceptable safety/tolerability of alb-IFN 900-1500 microg every 2 weeks and 1200-1500 microg every 4 weeks. Based on the phase 2 data, alb-IFN 900 microg and 1200 microg every 2 weeks were selected for two ongoing phase 3 trials in IFN-naïve patients with genotype 1 and 2/3 CHC. Albinterferon alfa-2b exhibits high antiviral activity, and appears to offer safety/tolerability comparable to the current standard of care, and health-related quality-of-life benefits in patients with CHC. Its ability to maintain drug concentrations above the 90% effective concentration over prolonged dosing intervals suggests that it may be an ideal partner for combination therapy with direct antiviral agents in CHC. The results of the phase 3 trials are eagerly anticipated as they should greatly clarify the future role of alb-IFN in the treatment of CHC.
    Current Medical Research and Opinion 05/2009; 25(4):991-1002. · 2.37 Impact Factor


1 Download
Available from
Sep 16, 2014