Human polynucleotide phosphorylase (hPNPaseold-35): a potential link between aging and inflammation.

Abstract

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.

• Authors: Devanand Sarkar, Irina V Lebedeva, Luni Emdad, Dong-Chul Kang, Albert S Baldwin Jr, Paul B Fisher
• Journal: Cancer research (Cancer Res) Vol. 64 Issue 20 Pg. 7473-8 (Oct 15 2004) ISSN: 0008-5472 [Print] United States
• PMID: 15492272 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokine CCL5
• Interleukin-6
• Interleukin-8
• NF-kappa B
• RNA, Messenger
• Reactive Oxygen Species
• Exoribonucleases
• PNPT1 protein, human
• Matrix Metalloproteinase 3

Topics

• Adenoviridae (genetics)
• Cellular Senescence (physiology)
• Chemokine CCL5 (biosynthesis, genetics)
• Exoribonucleases (biosynthesis, genetics, physiology)
• HeLa Cells
• Humans
• Inflammation (enzymology, genetics)
• Interleukin-6 (biosynthesis, genetics)
• Interleukin-8 (biosynthesis, genetics)
• Matrix Metalloproteinase 3 (metabolism)
• NF-kappa B (metabolism)
• RNA, Messenger (biosynthesis, genetics)
• Reactive Oxygen Species (metabolism)