engleski

The role of tryptophan metabolism in iNOS transcription and NO production by chicken macrophage cell line HD11 upon IFN-gamma stimulation

The influence of de novo synthesis of NAD through the kynurenine (KYN) pathway of tryptophan (TRP) degradation on transcription of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) production in interferon gamma (IFN-g) stimulated and non-stimulated chicken macrophage cell line HD11 was investigated. Interferon gamma up regulation of iNOS transcription and NO production was dependent on the undisturbed flow through the KYN pathway. Inhibition of indoleamine-2, 3-dioxygenase, the rate limiting enzyme of TRP catabolism, by 1-methyl-L-tryptophan (1-mTRP) down regulated both iNOS transcription and NO production. Addition of KYN to 1-mTRP treated, IFN-g stimulated macrophages circumvented the down regulation of iNOS transcription and NO production. Inhibition of poly (ADP-ribose) polymerase (PARP), a nuclear enzyme involved in DNA repair, replication and transcription, which cleaves NAD into nicotinamide and ADP-ribose, abrogated TRP and KYN caused up regulation of iNOS transcription. Our results suggest that iNOS transcription is dependent on NAD synthesis in the KYN pathway, providing substrate for PARP to exert its transcription regulatory function.

iNOS; interferon gamma; nicotinamide adenine dinucleotide; poly(ADP-ribose) polymerase

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