Apoptosis in the thymus after intraperitoneal injection of rats with Trp-P-1.
3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), a contaminant in our daily diet, induces apoptosis in cultured immunocytes. In this study, Trp-P-1 (1 mg/kg) was injected intraperitoneally into male Wistar rats to investigate whether Trp-P-1 induces apoptosis in immune tissues in vivo. In the thymus, Trp-P-1 induced DNA fragmentation and morphological changes. Trp-P-1 also activated the initiator and executioner caspases, caspase-8 and -3, respectively, and activated caspase-3 in turn cleaved its intracellular substrate poly(ADP-ribose) polymerase 1 hr after injection. On the other hand, Trp-P-1 upregulated anti-apoptotic factors Bcl-2 and Bcl-XL and downregulated pro-apoptotic factor Bax in mitochondria 1 hr after injection, indicating that Trp-P-1 also stimulated anti-apoptotic signals. Trp-P-1 activated the serine-threonine protein kinase Akt, which is known to be an anti-apoptotic protein, and increased the DNA binding activities of apoptosis-associated transcription factors NF-kappaB and AP-1. In addition to the thymus, increases in the activities of these transcription factors were also observed in the spleen and in mononuclear cells from the blood. Therefore, Trp-P-1 activates both pro- and anti-apoptotic signals in vivo in the immune system, particularly in the thymus, and the former signal overcomes the latter.
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002243:Carbolines; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D053938:DNA Fragmentation; D015536:Down-Regulation; D004789:Enzyme Activation; D008297:Male; D008854:Microscopy, Electron; D009153:Mutagens; D018384:Oxidative Stress; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000378:metabolism; D013950:Thymus Gland / Q000187:drug effects / Q000473:pathology*; D013997:Time Factors; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein
C494828:Bax protein, rat; D002243:Carbolines; D009153:Mutagens; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D011065:Poly(ADP-ribose) Polymerases; C505528:Casp8 protein, rat; C506435:Casp9 protein, rat; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; C019132:3-amino-1,4-dimethyl-5H-pyrido(4,3-b)indole