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* Children’s Hospital, Ludwig-Maximilians University, Munich, Germany;
Institute for Biochemistry and Biology, University of Potsdam, Potsdam, Germany;
University of Colorado Health Sciences Center, Denver, CO 80262; and
Department of Biomedical Science and Technology, Konkuk University, Seoul, Korea
The IL-1 family member 7b (IL-1F7b) is a novel homolog of the IL-1 cytokine family discovered by computational cloning. We have reported that IL-1F7b shares critical amino acid residues with IL-18 and binds the IL-18-binding protein; in doing so, IL-1F7b augments the inhibition of IFN-
by the IL-18-binding protein. IL-1F7b also binds IL-18R
but neither induces signal nor acts as a receptor antagonist. Hence, the function of IL-1F7b remains unknown. In the present study, we analyzed the intracellular expression pattern of IL-1F7b. Using two variants of GFP fusion constructs of human IL-1F7b stably expressed in RAW macrophages, only the postcleavage mature form of the IL-1F7b precursor—but not the N-terminal propiece—specifically translocates to the nucleus following LPS stimulation. IL-1F7b, like IL-1β, IL-18, and IL-33, is processed by caspase-1 to generate the mature cytokines. Therefore, we tested whether caspase-1-mediated cleavage of the IL-1F7b precursor is required for mature IL-1F7b to translocate actively into the nucleus. Indeed, a specific caspase-1 inhibitor markedly reduced nuclear entry of IL-1F7b. In stable transfectants of human IL-1F7b in RAW macrophages stimulated with LPS, levels of TNF-, IL-1, IL-6, as well as the chemokine MIP-2, were substantially reduced (72–98%) compared with LPS-stimulated cells transfected with the empty plasmid. These results demonstrate that IL-1F7b translocates to the nucleus after caspase-1 processing and may act as a transcriptional modulator reducing the production of LPS-stimulated proinflammatory cytokines, consistent with IL-1F7b being an anti-inflammatory member of the IL-1 family.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Deutsche Forschungsgemeinschaft (BU-1222/3-1 and BU-1222/3-2; to P.B.) and by National Institutes of Health Grant AI-15614 (to C.A.D.). S.-H. K. was supported by a Korea Science and Engineering Foundation grant funded by the Korean government (MOST). M.F.N. was supported by Deutsche Forschungsgemeinschaft (MN-747/1-1).
2 Address correspondence and reprint requests to Dr. Philip Bufler, Children’s Hospital, Ludwig-Maximilians University, Lindwurmstrasse 4, 80337 Munich, Germany. E-mail address: philip.bufler{at}med.uni-muenchen.de
3 Abbreviations used in this paper: IL-18BP, IL-18-binding protein; CFP, cyan fluorescence protein; YFP, yellow fluorescence protein.
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