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The Journal of Immunology, Vol 155, Issue 6 2858-2865, Copyright © 1995 by American Association of Immunologists

ARTICLES

Nitric oxide induces apoptosis in mouse thymocytes

K Fehsel, KD Kroncke, KL Meyer, H Huber, V Wahn and V Kolb-Bachofen
Institute of Immunobiology, Heinrich Heine University, Dusseldorf, Germany.

Nitric oxide (NO) produced at high concentrations by the inducible NO synthase is an important effector molecule involved in immune regulation and defense. We have examined whether NO represents a signal for triggering apoptosis in thymocytes. Freshly isolated thymocytes were incubated with different chemical NO donors for various intervals. Apoptosis was determined by detection of DNA strand breaks with in situ nick translation. All NO donors induced thymocyte apoptosis with 30% positive thymocytes vs 10% in controls after 8 h. Apoptosis was prevented by addition of ZnSO4. Short-term pre-exposure to NO resulted in protection from apoptosis induced by glucocorticoids comparable with the protective effect of heat shock. Flow cytometry revealed that NO treatment as well as heat shock or dexamethasone incubation is accompanied by reduction in the CD4+ CD8+ thymocyte subpopulation. Apoptosis induction was accompanied by increased expression of p53, as detected by PCR analysis 2 h after NO donor addition. In vivo treatment of mice with endotoxin results in increased thymic apoptosis. Focal apoptosis was found to occur in close proximity to blood vessels 18 h after LPS treatment. Capillary endothelium and dendritic cells adjacent to apoptotic foci were found to stain strongly for inducible NO synthase expression. Furthermore, in an in vitro experiment using cocultures of thymocytes with LPS/cytokine-activated endothelial cells expressing inducible NO synthase, a significantly increased rate of thymocyte apoptosis was found, and this could be prevented completely by inhibiting NO production. Addition of dexamethasone to these cocultures did not lead to a further increase in the percentage of apoptotic thymocytes, underlining the protective effect of NO on dexamethasone-induced apoptosis.


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J. Immunol., March 15, 1998; 160(6): 2590 - 2596.
[Abstract] [Full Text] [PDF]

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Y.-M. Kim, R. V. Talanian, and T. R. Billiar
Nitric Oxide Inhibits Apoptosis by Preventing Increases in Caspase-3-like Activity via Two Distinct Mechanisms
J. Biol. Chem., December 5, 1997; 272(49): 31138 - 31148.
[Abstract] [Full Text] [PDF]

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J. B. Mannick, X. Q. Miao, and J. S. Stamler
Nitric Oxide Inhibits Fas-induced Apoptosis
J. Biol. Chem., September 26, 1997; 272(39): 24125 - 24128.
[Abstract] [Full Text] [PDF]

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W. Poluha, C. M. Schonhoff, K. S. Harrington, M. B. Lachyankar, N. E. Crosbie, D. A. Bulseco, and A. H. Ross
A Novel, Nerve Growth Factor-activated Pathway Involving Nitric Oxide, p53, and p21WAF1 Regulates Neuronal Differentiation of PC12 Cells
J. Biol. Chem., September 19, 1997; 272(38): 24002 - 24007.
[Abstract] [Full Text] [PDF]

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Y.-M. Kim, M. E. de Vera, S. C. Watkins, and T. R. Billiar
Nitric Oxide Protects Cultured Rat Hepatocytes from Tumor Necrosis Factor-alpha -induced Apoptosis by Inducing Heat Shock Protein 70Expression
J. Biol. Chem., January 10, 1997; 272(2): 1402 - 1411.
[Abstract] [Full Text] [PDF]

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Donald. L. Sorrells, C. Friend, U. Koltuksuz, A. Courcoulas, P. Boyle, M. Garrett, S. Watkins, M. I. Rowe, and H. R. Ford
Inhibition of Nitric Oxide With Aminoguanidine Reduces Bacterial Translocation After Endotoxin Challenge In Vivo
Arch Surg, November 1, 1996; 131(11): 1155 - 1163.
[Abstract] [PDF]

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B. Brune
Bcl-2 Protects Macrophages from Nitric Oxide-induced Apoptosis
J. Biol. Chem., August 16, 1996; 271(33): 20192 - 20197.
[Abstract] [Full Text] [PDF]


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