Significance of protein tyrosine kinase/protein tyrosine phosphatase balance in the regulation of NF-kappaB signaling in the inflammatory process and aging.

Protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) are well recognized for the essential roles they play in signal transduction by maintaining proper balance under redox status. One of the major transcription factors known to be involved in aging is the redox-sensitive proinflammatory NF-kappaB, which could be modulated by the activities of PTKs and PTPs. This study delved into a molecular inquiry of the PTK/PTP balance, which is affected by oxidative stress-induced redox changes during aging. To obtain the underlying molecular clues, we assessed the PTK/PTP status in the aged rat kidney utilizing aging-retarding calorie restriction and inflammation-triggering LPS paradigms. The results suggest that reactive species increase PTK activation, which is counterbalanced by decreased PTP, leading to a shift in the PTK/PTP balance. This shift in the balance was confirmed by free radical-generating AAPH injected into mouse or HEK293T cells, which led to NF-kappaB activation. To strengthen the findings, we perturbed the PTK/PTP balance using a PTP inhibitor, Na(3)VO(4), which caused NF-kappaB activation through phosphorylated NIK/IKK and MAPKs. Thus, our data suggest, for the first time, that the delicate balance between PTK and PTP is disturbed during aging and inflammation, both of which lead to NF-kappaB activation via NIK/IKK and MAPKs.