Increased mortality and impaired clonal deletion after staphylococcal enterotoxin B injection in old mice: relation to cytokines and nitric oxide production.
In the present study peripheral T cell tolerance and the occurrence of shock were evaluated in young and old mice after injection of Staphylococcal enterotoxin B (SEB). In young mice SEB immunization leads to tolerance based on deletion and anergy of SEB-reactive V beta 8+ T cells. With aging, mice developed resistance to SEB-induced deletion of V beta 8+ T cells as well as a high sensitivity to toxic shock. Compared to young mice, older mice injected with SEB showed increased serum levels of interferon-gamma (IFN-gamma), interleukin-2 (IL-2) and IL-4. These results were confirmed by reverse transcription-polymerase chain reaction (RT-PCR), as splenic mRNA levels taken 2 h after SEB injection showed higher values of IL-2, IL-4, and IFN-gamma in old mice. In contrast, mRNA levels for FasL and tumour necrosis factor-alpha (TNF-alpha) were lower. No difference in IL-10 mRNA was found. Compared to young mice, old mice showed a high, but statistically not significantly different (P = 0.20), production of nitric oxide (NO). Blocking of IFN-gamma with antibodies or reducing IFN-gamma by depletion of natural killer (NK) cells resulted, respectively, in a complete or partial protection against mortality in aged mice. Suppressing the NO production by the NO synthase inhibitor N-nitro-L-arginine methylester (L-NAME) increased the mortality in both young and old mice, and abrogated clonal deletion in the surviving young mice. In conclusion, in young mice NO production is a key factor in the protection against mortality and the development of clonal deletion after SEB injection. The higher mortality seen in older mice is mainly related to the elevated production of IFN-gamma and occurs despite a sufficient production of NO. The decreased clonal deletion of old mice may be related to their decreased expression of Fas ligand or TNF-alpha after SEB injection.
Kuschnaroff
L M
LM
Laboratory for Experimental Transplantation, Rega Institute, University of Leuven, Belgium.
Goebels
J
J
Valckx
D
D
Heremans
H
H
Matthys
P
P
Waer
M
M
D000375:Aging / Q000276:immunology*; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology / Q000494:pharmacology / Q000633:toxicity*; D017635:Clonal Anergy / Q000187:drug effects; D017637:Clonal Deletion / Q000187:drug effects*; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D004768:Enterotoxins / Q000276:immunology / Q000494:pharmacology / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053222:Fas Ligand Protein; D005786:Gene Expression Regulation; D007114:Immunization; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012772:Shock, Septic / Q000139:chemically induced / Q000276:immunology* / Q000503:physiopathology; D013211:Staphylococcus aureus / Q000276:immunology; D018089:Superantigens / Q000276:immunology / Q000494:pharmacology / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
D000942:Antigens, Bacterial; D016207:Cytokines; D004768:Enterotoxins; D004791:Enzyme Inhibitors; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D018089:Superantigens; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015847:Interleukin-4; D009569:Nitric Oxide; C031818:enterotoxin B, staphylococcal; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester