SIRT1 longevity factor suppresses NF‐κB ‐driven immune responses: regulation of aging via NF‐κB acetylation?

Abstract

The aging process involves changes in immune regulation, i.e. adaptive immunity declines whereas innate immunity becomes activated. NF-kappaB signaling is the master regulator of the both immune systems. Two recent articles highlight the role of the NF-kappaB system in aging and immune responses. Adler et al showed that the NF-kappaB binding domain is the genetic regulatory motif which is most strongly associated with the aging process. Kwon et al studying HIV-1 infection and subsequent immune deficiency process demonstrated that HIV-1 Tat protein binds to SIRT1 protein, a well-known longevity factor, and inhibits the SIRT1-mediated deacetylation of the p65 component of the NF-kappaB complex. As a consequence, the transactivation efficiency of the NF-kappaB factor was greatly potentiated, leading to the activation of immune system and later to the decline of adaptive immunity. These observations support the scenario where immune responses and aging process can be enforced by the potentiation of NF-kappaB transactivation efficiency. Longevity factors, such as SIRT1 and its activators, might regulate the efficiency of the NF-kappaB signaling, the major outcome of which is inflamm-aging via proinflammatory responses.

Sirtuin 1: A Target for Kidney Diseases

“…The most studied one is the heterodimer consisting of the p65 and p50 protein. SIRT1 binds and deacetylates Lys310 of p65 subunit, inhibiting transcriptional activity (16,75). Furthermore, SIRT1 deletion activated NF-κB because of the increased NF-κB acetylation, resulting in enhanced inflammation and aggravated acute kidney injury after lipopolysaccharide challenge (24).…”

Histone deacetylases and the immunological network: implications in cancer and inflammation

“…Finally, we discuss the changes in HDACs that occur in immune cell-derived tumors, such as leukemias and lymphomas, and how the use of HDIs may potentially tip the balance toward effective antitumor responses due to their effects on tumor cells and the host's immune cells. As there are several excellent recent reviews that discuss the topic of Class III HDACs (sirtuins) in immune response and inflammation (Salminen et al, 2008;Finkel et al, 2009;Natoli, 2009), this review will focus more on the Class I and II enzymes.…”

Sirt1 protects against thrombomodulin down-regulation and lung coagulation after particulate matter exposure

“…[21][22][23][24][25][26] NF-B, a transcription factor that regulates inflammatory responses, is an endogenous substrate for Sirt1. [27][28][29][30] It has been reported that Sirt1 deacetylates NF-B, thereby inhibiting its activity in several in vitro and in vivo systems. [27][28][29][30] NF-B activation has been reported to suppress TM expression, 31,32 implying that Sirt1 may be involved in protection against both inflammation and coagulation.…”