title: Interferon-γ- and glucocorticoid-mediated pathways synergize to enhance death of CD4(+) CD8(+) thymocytes during Salmonella enterica serovar Typhimurium infection.
abstract: Thymic atrophy is known to occur during infections; however, there is limited understanding of its causes and of the cross-talk between different pathways. This study investigates mechanisms involved in thymic atrophy during a model of oral infection by Salmonella enterica serovar Typhimurium (S. typhimurium). Significant death of CD4(+) CD8(+) thymocytes, but not of single-positive thymocytes or peripheral lymphocytes, is observed at later stages during infection with live, but not heat-killed, bacteria. The death of CD4(+) CD8(+) thymocytes is Fas-independent as shown by infection studies with lpr mice. However, apoptosis occurs with lowering of mitochondrial potential and higher caspase-3 activity. The amounts of cortisol, a glucocorticoid, and interferon-γ (IFN-γ), an inflammatory cytokine, increase upon infection. To investigate the functional roles of these molecules, studies were performed using Ifnγ(-/-) mice together with RU486, a glucocorticoid receptor antagonist. Treatment of C57BL/6 mice with RU486 does not affect colony-forming units (CFU), amounts of IFN-γ and mouse survival; however, there is partial rescue in thymocyte death. Upon infection, Ifnγ(-/-) mice display higher CFU and lower survival but more surviving thymocytes are recovered. However, there is no difference in cortisol amounts in C57BL/6 and Ifnγ(-/-) mice. Importantly, the number of CD4(+) CD8(+) thymocytes is significantly higher in Ifnγ(-/-) mice treated with RU486 along with lower caspase-3 activity and mitochondrial damage. Hence, endogenous glucocorticoid and IFN-γ-mediated pathways are parallel but synergize in an additive manner to induce death of CD4(+) CD8(+) thymocytes during S. typhimurium infection. The implications of this study for host responses during infection are discussed.
authors.affiliation: Department of Biochemistry, Indian Institute of Science, Bangalore, India.
authors.forename: Mukta
authors.initials: M
authors.lastname: Deobagkar-Lele
authors.forename: Suni K
authors.initials: SK
authors.lastname: Chacko
authors.forename: Emmanuel S
authors.initials: ES
authors.lastname: Victor
authors.forename: Jayachandra C
authors.initials: JC
authors.lastname: Kadthur
authors.forename: Dipankar
authors.initials: D
authors.lastname: Nandi
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology; D016827:CD8 Antigens / Q000235:genetics / Q000276:immunology; D053148:Caspase 3 / Q000235:genetics / Q000276:immunology; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects; D006727:Hormone Antagonists / Q000494:pharmacology; D006854:Hydrocortisone / Q000096:biosynthesis / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D015735:Mifepristone / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D012481:Salmonella Infections, Animal / Q000276:immunology* / Q000382:microbiology / Q000401:mortality; D012486:Salmonella typhimurium / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells; D015996:Survival Rate; D060168:Thymocytes / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D013950:Thymus Gland / Q000276:immunology* / Q000382:microbiology / Q000473:pathology
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D006727:Hormone Antagonists; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D007371:Interferon-gamma; D053148:Caspase 3; D006854:Hydrocortisone