Nitric oxide inhibits spleen cell proliferative response after burn injury by inducing cytostasis, apoptosis, and necrosis of activated T lymphocytes: role of the guanylate cyclase.
We previously showed that an overproduction of nitric oxide (NO) by macrophages was responsible for the collapse of lymphoproliferative responses after burn injury in rats. First, we demonstrate here that 10 days post-burn, the inhibition of splenocyte response to concanavalin-A results from cytostatic, apoptotic, and necrotic effects of NO on activated T cells. This was evidenced by various criteria at the levels of DNA, mitochondria, and plasma membrane. Inhibition of NO synthase by S-methylisothiourea (10 microM) normalized all the parameters. Second, we show that two soluble guanylate cyclase (sGC) inhibitors, LY83583 and ODQ, restored the proliferative response in a concentration-dependent manner. LY83583 (0.5 microM) rescued T cells from apoptosis. Similar results were obtained with KT5823 (5 microM) a specific inhibitor of protein kinase G (PKG). In contrast, neither LY83583 nor KT5823 inhibited NO-induced necrosis. These results suggest that NO blocked T cells in the G1 phase and induced apoptosis through a sGC-PKG-dependent pathway and necrosis through an independent one.
Département de Pharmacologie, CNRS UPRES-A 8068, Pavillon Gustave Roussy, Hôpital Cochin, 27 rue du Faubourg Saint Jacques, 75679 Paris cedex 14, France. valentilio@yahoo.fr
Lionel
L
Valenti
Jacques
J
Mathieu
Yves
Y
Chancerelle
Maryse
M
Levacher
Brigitte
B
Chanaud
Martine
M
De Sousa
Suzanne
S
Strzalko
Anh Tuan
AT
Dinh-Xuan
Jean-Paul
JP
Giroud
Irène
I
Florentin
D000470:Alkaloids / Q000494:pharmacology; D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002056:Burns / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D002227:Carbazoles; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000502:physiology*; D007211:Indoles; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D009336:Necrosis; D009569:Nitric Oxide / Q000502:physiology*; D010069:Oxadiazoles / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012867:Skin; D013154:Spleen / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000201:enzymology* / Q000276:immunology*
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000470:Alkaloids; D000634:Aminoquinolines; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D010069:Oxadiazoles; D047428:Protein Kinase Inhibitors; D011810:Quinoxalines; C073601:KT 5823; D009569:Nitric Oxide; C041715:6-anilino-5,8-quinolinedione; D006162:Guanylate Cyclase