title: Lymphocyte-mediated macrophage apoptosis during IL-12 stimulation.
abstract: In contrast to the well known immunostimulatory roles of IL-12, little has been known about its immunosuppressive roles. In the present study, IL-12-activated lymphocyte-mediated macrophage apoptosis was investigated by employing murine lymphocyte/macrophage cocultures. IL-12-activated lymphocytes and their culture supernatants induced an inducible nitric oxide synthase (iNOS)-mediated nitric oxide (NO) synthesis in macrophages. The NO synthesis was markedly inhibited by blocking antibodies to IFN-γ and TNF-α, suggesting the key role of these lymphocyte cytokines in mediating the NO synthesis. The endogenously produced NO inhibited macrophage proliferation, and induced apoptosis in concordance with the accumulation of p53, phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and DR5, and the activation of caspase-3, processes that were inhibited by N(G)-monomethyl-l-arginine, aminoguanidine (NO synthase inhibitors) and 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (an NO scavenger). These results were further supported by the findings obtained from the experiments employing IFN-γ-knockout and iNOS-knockout mice. Our study demonstrated a novel, non-contact-dependent mechanism of macrophage suppression by IL-12-activated lymphocytes: induction of growth inhibition and apoptosis of macrophages due to endogenous NO synthesis induced by cytokines secreted from IL-12-activated lymphocytes.
authors: Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Jeonbuk 561-180, Republic of Korea; Biomedical Research Institute, Chonbuk National University Hospital, Jeonju, Jeonbuk 561-712, Republic of Korea; Advanced Research Center for Cancer, Chonbuk National University Hospital, Jeonju, Jeonbuk 561-712, Republic of Korea.
authors: Joo-Yun
authors: JY
authors: Yim
authors: Su-Jin
authors: SJ
authors: Yang
authors: Jun-Mo
authors: JM
authors: Yim
authors: Min-Young
authors: MY
authors: Song
authors: Hye-Won
authors: HW
authors: Rho
authors: Sung Kyun
authors: SK
authors: Yim
authors: Yeon-Hee
authors: YH
authors: Han
authors: So Yeon
authors: SY
authors: Jeon
authors: Hee Sun
authors: HS
authors: Kim
authors: Ho-Young
authors: HY
authors: Yhim
authors: Na-Ri
authors: NR
authors: Lee
authors: Eun-Kee
authors: EK
authors: Song
authors: Jae-Yong
authors: JY
authors: Kwak
authors: Myung-Hee
authors: MH
authors: Sohn
authors: Chang-Yeol
authors: CY
authors: Yim
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D001565:Benzoates / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D006146:Guanidines / Q000378:metabolism; D007093:Imidazoles / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D019323:omega-N-Methylarginine / Q000378:metabolism
chemical_list: D019138:Antibodies, Blocking; D001565:Benzoates; D006146:Guanidines; D007093:Imidazoles; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; C079393:1,3-dihydroxy-4,4,5,5-tetramethyl-2-(4-carboxyphenyl)tetrahydroimidazole; D018664:Interleukin-12; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D053148:Caspase 3; C004479:pimagedine
keywords: 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide; Apoptosis; B6; C57BL/6J; Carboxy-PTIO; FCS; FITC; IFN-γ; IL-12; Interferon-γ; LPS; Lymphocyte; MAb; MLA; Macrophage; N(G)-monomethyl-l-arginine; NO; NOS; PBS; PE; PTEN; ROS; SD; TNF-α; fetal calf serum; fluorescein isothiocyanate; iNOS; inducible nitric oxide synthase; interferon-γ; lipopolysaccharide; monoclonal antibody; nitric oxide; nitric oxide synthase; phosphatase and tensin homologue deleted on chromosome 10; phosphate-buffered saline; phycoerythrin; reactive oxygen species; standard deviation; tumor necrosis factor-α