Independent and synergistic effects of interleukin-18 and interleukin-12 in augmenting cytotoxic T lymphocyte responses and IFN-gamma production in aging.
Aged mice exhibit diminished CD8(+) cytotoxic T lymphocyte (CTL) response to influenza virus. Previously, interleukin-12 (IL-12) was shown to partially restore in vitro influenza virus-specific CD8(+) CTL activity and interferon-gamma (IFN-gamma) production in aged mice. The present study investigated IL-18 production and its ability to collaborate with IL-12 to enhance these responses to the levels of young mice. IL-18 protein production and mRNA expression in influenza virus-specific CTL from aged mice were higher than from young mice. In contrast, IL-18 receptor (IL-18R) mRNA expression was significantly reduced in CD8(+) CTL from aged mice. Generation of CTL in the presence of IL-12 alone caused a significant increase in IFN-gamma production in both old and young mice. IL-18 treatment alone significantly increased IFN-gamma in CTL from young but not old mice. However, a combination of IL-18 and IL-12 significantly increased IFN-gamma in both old and young mice. IL-18 and IL-12, either alone or in combination, stimulated significant influenza virus-specific cytotoxicity in both old and young mice, but no significant synergistic effect was observed. These results represent an initial demonstration of downregulated IL-18R expression in aging mice and are consistent with age-related cytotoxic T lymphocyte 1 (Tc1) deficiency. Potentially, IL-18 and IL-12 can augment IFN-gamma production and reverse CD8(+) CTL deficiency in aging, independently or synergistically.
Zhang
Y
Y
Influenza Research Center, Respiratory Pathogens Research Unit, Department of Microbiology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
Wang
Y
Y
Gilmore
X
X
Xu
K
K
Mbawuike
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IN
D000375:Aging / Q000276:immunology*; D000818:Animals; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D029521:Alphainfluenzavirus / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000494:pharmacology*; D020382:Interleukin-18 / Q000096:biosynthesis / Q000494:pharmacology*; D053727:Interleukin-18 Receptor alpha Subunit; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics; D053724:Receptors, Interleukin-18; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*
C508573:Il18r1 protein, mouse; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18; D018664:Interleukin-12; D007371:Interferon-gamma