IL-1 signaling cascade in liver cells and the involvement of a soluble form of the IL-1 receptor accessory protein.
The proinflammatory cytokine IL-1 induces the biosynthesis of a number of immunologically important proteins during infection, tissue damage, and/or stress, in part through the activation of the transcription factor NF-kappaB. Signal transduction is initiated at the cell membrane by complex formation between extracellular IL-1 and the transmembrane IL-1R type I (IL-1RI) and IL-1R accessory protein (IL-1RAcP). The intracellular signaling cascade involves recruitment of two IL-1R-associated kinases, IRAK1 and IRAK2, and the adapter protein MyD88, events which are dependent on the intracellular domain of membrane-bound IL-1RAcP (mIL-1RAcP). In mouse liver, IL-1RAcP is expressed as a soluble protein (sIL-1RAcP), the function of which is unknown. We have cloned the human sIL-1RAcP and established by sequence analysis that the human sIL-1RAcP mRNA arises from alternative splicing of the IL-1RAcP gene (shown here to encompass 12 exons spanning more than 56 kb). Furthermore, we demonstrate that human HepG2 hepatoma cells express both mIL-1RAcP and sIL-1RAcP and that signal transduction in these cells is mediated through IRAK1, IRAK2, and MyD88. We show that phorbol esters induce a change in the pre-mRNA splice pattern such that sIL-1RAcP mRNA becomes the dominant form. Overexpression of a membrane-anchored fusion protein of sIL-1RAcP and MHC in HepG2 cells inhibits IL-1-mediated NF-kappaB activation, whereas coexpression of IL-1RI with membrane-anchored sIL-1RAcP restores the capacity of the cells to respond to IL-1. This suggests that sIL-1RAcP may act as an inhibitor of IL-1 by directly interacting with IL-1RI to abolish its capacity to transduce signal.
Jensen
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Department of Pharmacology, Center for Pharmacogenetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. jensen@pharm.med.upenn.edu
Muzio
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Mantovani
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Whitehead
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D000209:Acute-Phase Proteins / Q000096:biosynthesis / Q000235:genetics; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism; D002462:Cell Membrane / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003001:Cloning, Molecular; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism / Q000502:physiology*; D053577:Interleukin-1 Receptor Accessory Protein; D008099:Liver / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D014176:Protein Biosynthesis; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D017472:Receptors, Interleukin-1 / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D012995:Solubility; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000209:Acute-Phase Proteins; C507765:IL1RAP protein, human; C507767:Il1rap protein, mouse; D007375:Interleukin-1; D053577:Interleukin-1 Receptor Accessory Protein; D011506:Proteins; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1