Human polynucleotide phosphorylase (hPNPaseold-35): a potential link between aging and inflammation.
Chronic inflammation is a characteristic feature of aging, and the relationship between cellular senescence and inflammation, although extensively studied, is not well understood. An overlapping pathway screen identified human polynucleotide phosphorylase (hPNPase(old-35)), an evolutionary conserved 3',5'-exoribonuclease, as a gene up-regulated during both terminal differentiation and cellular senescence. Enhanced expression of hPNPase(old-35) via a replication-incompetent adenovirus (Ad.hPNPase(old-35)) in human melanoma cells and normal human melanocytes results in a characteristic senescence-like phenotype. Reactive oxygen species (ROS) play a key role in the induction of both in vitro and in vivo senescence. We now document that overexpression of hPNPase(old-35) results in increased production of ROS, leading to activation of the nuclear factor (NF)-kappaB pathway. Ad.hPNPase(old-35) infection promotes degradation of IkappaBalpha and nuclear translocation of NF-kappaB and markedly increases binding of the transcriptional activator p50/p65. The generation of ROS and activation of NF-kappaB by hPNPase(old-35) are prevented by treatment with a cell-permeable antioxidant, N-acetyl-l-cysteine. Infection with Ad.hPNPase(old-35) enhances the production of interleukin (IL)-6 and IL-8, two classical NF-kappaB-responsive cytokines, and this induction is inhibited by N-acetyl-l-cysteine. A cytokine array reveals that Ad.hPNPase(old-35) infection specifically induces the expression of proinflammatory cytokines, such as IL-6, IL-8, RANTES, and matrix metalloproteinase (MMP)-3. We hypothesize that hPNPase(old-35) might play a significant role in producing pathological changes associated with aging by generating proinflammatory cytokines via ROS and NF-kappaB. Understanding the relationship between hPNPase(old-35) and inflammation and aging provides a unique opportunity to mechanistically comprehend and potentially intervene in these physiologically important processes.
Sarkar
Devanand
D
Department of Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, New York, USA.
Lebedeva
Irina V
IV
Emdad
Luni
L
Kang
Dong-Chul
DC
Baldwin
Albert S
AS
Fisher
Paul B
PB
D000256:Adenoviridae / Q000235:genetics; D016922:Cellular Senescence / Q000502:physiology; D018946:Chemokine CCL5 / Q000096:biosynthesis / Q000235:genetics; D005095:Exoribonucleases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D024101:Mitochondrial Proteins
D018946:Chemokine CCL5; D005095:Exoribonucleases; D015850:Interleukin-6; D016209:Interleukin-8; D019278:Matrix Metalloproteinase 3; D016328:NF-kappa B; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C476417:PNPT1 protein, human; D024101:Mitochondrial Proteins