title: IL-18 up-regulates perforin-mediated NK activity without increasing perforin messenger RNA expression by binding to constitutively expressed IL-18 receptor.
abstract: IL-18 is a powerful inducer of IFN-gamma production, particularly in collaboration with IL-12. IL-18, like IL-12, also augments NK activity. Here we investigated the molecular mechanism underlying the up-regulation of killing activity of NK cells by IL-18. IL-18, like IL-12, dose dependently enhanced NK activity of splenocytes. This action was further enhanced by costimulation with IL-12. Treatment with anti-IL-2R Ab did not affect IL-18- and/or IL-12-augmented NK activity, and splenocytes from IFN-gamma-deficient mice showed enhanced NK activity following stimulation with IL-12 and/or IL-18. Splenocytes from the mice deficient in both IL-12 and IL-18 normally responded to IL-18 and/or IL-12 with facilitated NK activity, suggesting that functional NK cells develop in the absence of IL-12 and IL-18. IL-18R, as well as IL-12R mRNA, was constitutively expressed in splenocytes from SCID mice, which lack T cells and B cells but have intact NK cells, and in those from IL-12 and IL-18 double knockout mice. NK cells isolated from SCID splenocytes expressed IL-18R on their surface. IL-18, in contrast to IL-12, did not enhance mRNA expression of perforin, a key molecule for exocytosis-mediated cytotoxicity. However, pretreatment with concanamycin A completely inhibited this IL-18- and/or IL-12-augmented NK activity. Furthermore, IL-18, like IL-12, failed to enhance NK activity of splenocytes from perforin-deficient mice. These data suggested that NK cells develop and express IL-12R and IL-18R in the absence of IL-12 or IL-18, and that both IL-18 and IL-12 directly and independently augment perforin-mediated cytotoxic activity of NK cells.
authors.affiliation: Third Department of Internal Medicine, Laboratory of Host Defenses Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Hyodo
authors.forename: K
authors.initials: K
authors.lastname: Matsui
authors.forename: N
authors.initials: N
authors.lastname: Hayashi
authors.forename: H
authors.initials: H
authors.lastname: Tsutsui
authors.forename: S
authors.initials: S
authors.lastname: Kashiwamura
authors.forename: H
authors.initials: H
authors.lastname: Yamauchi
authors.forename: K
authors.initials: K
authors.lastname: Hiroishi
authors.forename: K
authors.initials: K
authors.lastname: Takeda
authors.forename: Y
authors.initials: Y
authors.lastname: Tagawa
authors.forename: Y
authors.initials: Y
authors.lastname: Iwakura
authors.forename: N
authors.initials: N
authors.lastname: Kayagaki
authors.forename: M
authors.initials: M
authors.lastname: Kurimoto
authors.forename: H
authors.initials: H
authors.lastname: Okamura
authors.forename: T
authors.initials: T
authors.lastname: Hada
authors.forename: H
authors.initials: H
authors.lastname: Yagita
authors.forename: S
authors.initials: S
authors.lastname: Akira
authors.forename: K
authors.initials: K
authors.lastname: Nakanishi
authors.forename: K
authors.initials: K
authors.lastname: Higashino
mesh_terms: D000818:Animals; D001483:Base Sequence; D003602:Cytotoxicity, Immunologic; D017931:DNA Primers / Q000235:genetics; D005260:Female; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics; D018664:Interleukin-12 / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology; D020382:Interleukin-18 / Q000172:deficiency / Q000378:metabolism / Q000494:pharmacology*; D053727:Interleukin-18 Receptor alpha Subunit; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000378:metabolism*; D053707:Receptors, Interleukin-12; D053724:Receptors, Interleukin-18