Archives of medical research · 2008
Activation and overexpression of PARP-1 in circulating mononuclear cells promote TNF-alpha and IL-6 expression in patients with unstable angina.
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Huang Dan, Yang Chong-zhe, Yao Lan, Wang Yan, Liao Yu-hua, Huang Kai
Аннотация
BACKGROUND: Proinflammatory cytokines are involved in the development of unstable angina (UA). Poly(ADP-ribose) polymerase-1 (PARP-1) contributes importantly to regulating the transcription of inflammatory cytokines. This study aims to investigate the relationship of PARP-1 in circulating mononuclear cells (MNCs) and plasma TNF-alpha and IL-6 in UA patients and to elucidate the mechanism that PARP-1 promotes TNF-alpha and IL-6 expression via NF-kappaB pathway.
METHODS: Twenty six Braunwald class IIIB UA patients, 25 stable angina patients and 25 healthy volunteers were enrolled in this study. Plasma TNF-alpha and IL-6 were determined with ELISA. Circulating MNCs were analyzed for PARP activity, PARP-1 expression and NF-kappaB DNA binding activity. MNCs from healthy subjects were cultured to investigate the direct effects of PARP-1 on NF-kappaB DNA binding activity and the expression of TNF-alpha and IL-6.
RESULTS: PARP activity and PARP-1 expression in circulating MNCs were increased and positively correlated with plasma TNF-alpha and IL-6, respectively, in UA patients. Spontaneous NF-kappaB activation in MNCs was demonstrated in UA patients. In cultured MNCs from healthy subjects, inhibition of PARP-1 prevented lipopolysaccharide-induced increase in DNA binding activity of NF-kappaB and the expression of TNF-alpha and IL-6. Supershift assay demonstrated that PARP-1 was a component of NF-kappaB/DNA complex. Addition of recombinant human PARP-1 protein to nuclear extracts of MNCs significantly increased the DNA binding activity of NF-kappaB.
CONCLUSIONS: Activation and overexpression of PARP-1 are demonstrated in circulating MNCs of UA patients. Overexpressed PARP-1 promotes PARP-1/NF-kappaB/DNA complex formation, thereby enhancing the expression of TNF-alpha and IL-6 in circulating MNCs of UA patients.
METHODS: Twenty six Braunwald class IIIB UA patients, 25 stable angina patients and 25 healthy volunteers were enrolled in this study. Plasma TNF-alpha and IL-6 were determined with ELISA. Circulating MNCs were analyzed for PARP activity, PARP-1 expression and NF-kappaB DNA binding activity. MNCs from healthy subjects were cultured to investigate the direct effects of PARP-1 on NF-kappaB DNA binding activity and the expression of TNF-alpha and IL-6.
RESULTS: PARP activity and PARP-1 expression in circulating MNCs were increased and positively correlated with plasma TNF-alpha and IL-6, respectively, in UA patients. Spontaneous NF-kappaB activation in MNCs was demonstrated in UA patients. In cultured MNCs from healthy subjects, inhibition of PARP-1 prevented lipopolysaccharide-induced increase in DNA binding activity of NF-kappaB and the expression of TNF-alpha and IL-6. Supershift assay demonstrated that PARP-1 was a component of NF-kappaB/DNA complex. Addition of recombinant human PARP-1 protein to nuclear extracts of MNCs significantly increased the DNA binding activity of NF-kappaB.
CONCLUSIONS: Activation and overexpression of PARP-1 are demonstrated in circulating MNCs of UA patients. Overexpressed PARP-1 promotes PARP-1/NF-kappaB/DNA complex formation, thereby enhancing the expression of TNF-alpha and IL-6 in circulating MNCs of UA patients.