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)-κB pathway. Ad. hPNPase old-35 infection promotes degradation of IκBα and nuclear translocation of NF-κB and markedly increases binding of the transcriptional activator p50/p65. The generation of ROS and activation of NF-κB 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-κB-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-κB. 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.