title: Effects of interleukin-18 on natural killer cells: costimulation of activation through Fc receptors for immunoglobulin.
abstract: The antitumor activity of monoclonal antibodies is mediated by effector cells, such as natural killer (NK) cells, that express Fc receptors for immunoglobulin. Efficacy of monoclonal antibodies, including the CD20 antibody rituximab, could be improved by agents that augment the function of NK cells. Interleukin (IL)-18 is an immunostimulatory cytokine that has antitumor activity in preclinical models. The effects of IL-18 on NK cell function mediated through Fcγ receptors were examined. Human NK cells stimulated with immobilized IgG in vitro secreted IFN-γ as expected; such IFN-γ production was partially inhibited by blocking CD16 with monoclonal antibodies. IL-18 augmented IFN-γ production by NK cells stimulated with immobilized IgG or CD16 antibodies. NK cell IFN-γ production in response to immobilized IgG and/or IL-18 was inhibited by chemical inhibitors of Syk and several other kinases involved in CD16 signaling pathways. IL-18 augmented antibody-dependent cellular cytotoxicity (ADCC) of human NK cells against rituximab-coated Raji cells in vitro. IL-18 and rituximab acted synergistically to promote regression of human lymphoma xenografts in SCID mice. Inasmuch as IL-18 costimulates IFN-γ production and ADCC of NK cells activated through Fc receptors in vitro and augments antitumor activity of rituximab in vivo, it is an attractive cytokine to combine with monoclonal antibodies for treatment of human cancer.
authors.affiliation: Bone Marrow and Stem Cell Transplantation Program, Indianapolis, IN, USA. srivasts@iu.edu
authors.forename: Shivani
authors.initials: S
authors.lastname: Srivastava
authors.forename: David
authors.initials: D
authors.lastname: Pelloso
authors.forename: Hailin
authors.initials: H
authors.lastname: Feng
authors.forename: Larry
authors.initials: L
authors.lastname: Voiles
authors.forename: David
authors.initials: D
authors.lastname: Lewis
authors.forename: Zdenka
authors.initials: Z
authors.lastname: Haskova
authors.forename: Margaret
authors.initials: M
authors.lastname: Whitacre
authors.forename: Stephen
authors.initials: S
authors.lastname: Trulli
authors.forename: Yi-Jiun
authors.initials: YJ
authors.lastname: Chen
authors.forename: John
authors.initials: J
authors.lastname: Toso
authors.forename: Zdenka L
authors.initials: ZL
authors.lastname: Jonak
authors.forename: Hua-Chen
authors.initials: HC
authors.lastname: Chang
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Robertson
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007136:Immunoglobulins / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis; D020382:Interleukin-18 / Q000008:administration & dosage / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D008223:Lymphoma / Q000188:drug therapy / Q000276:immunology; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D011961:Receptors, Fc / Q000378:metabolism; D017452:Receptors, IgG / Q000276:immunology / Q000378:metabolism; D000069283:Rituximab; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D007074:Immunoglobulin G; D007136:Immunoglobulins; D020382:Interleukin-18; D011961:Receptors, Fc; D017452:Receptors, IgG; D000069283:Rituximab; D007371:Interferon-gamma