Compounds That Increase or Mimic Cyclic Adenosine Monophosphate Enhance Tristetraprolin Degradation in Lipopolysaccharide-Treated Murine J774 Macrophages

Abstract

Tristetraprolin (TTP) is a trans-acting factor that can regulate mRNA stability by binding to the cis-acting AU-rich element (ARE) in the 3Ј-untranslated region in mRNAs of certain transiently expressed genes. The best-studied target of TTP is tumor necrosis factor (TNF)-␣. By binding to ARE, TTP increases the degradation of TNF-␣ mRNA, thereby reducing the expression of TNF-␣. We examined the effects of cAMP analogs and the cAMP-elevating agents forskolin and ␤ 2 -agonists on lipopolysaccharide (LPS)-induced TTP mRNA and protein expression by quantitative real-time reverse transcriptase-polymerase chain reaction and Western blotting in activated macrophages. All of these agents caused a slight increase in LPSinduced expression of TTP mRNA. However, TTP protein levels were significantly reduced when the cells were treated with the combination of LPS and cAMP-elevating agent compared with LPS alone.and lactacystin increased TTP protein levels and abolished the effects of cAMP-enhancing compounds on TTP protein levels. The results suggest that mediators and drugs that enhance intracellular cAMP reduce TTP expression in macrophages exposed to inflammatory stimuli by increasing TTP degradation through the proteasome pathway.

Hepatocellular carcinoma and gene profiling: Back from perspective to reality

“…Our results showed that cAMP/PKA pathway was involved in the inhibitory effect of EX‐4 on LPS‐induced iNOS protein expression. These findings suggest that cAMP/PKA pathway is implicated in iNOS protein destabilization, which is supported by others' studies that cAMP enhanced tristetraprolin (TTP) protein degradation in LPS‐treated J774 macrophages without altering TTP mRNA degradation rate [Jalonen et al, 2008] and EX‐4 inhibited IL‐1β‐induced iNOS protein expression via cAMP/PKA system in INS‐1 beta‐cells [Kang et al, 2009], and also EX‐4 reduced high glucose‐induced thioredoxin interacting protein expression via cAMP/PKA signaling in INS‐1 cells [Shao et al, 2010].…”

MicroRNA-let-7a expression is increased in the mesangial cells of NZB/W mice and increases IL-6 productionin vitro

“…Although TTP expression in the NZB/W mouse model is currently unknown, studies using cells derived from TTP knockout mice have confirmed TTP is not the sole regulator of inflammatory mediator mRNA stability but have implicated it in the development of autoimmunity [61,62]. TTP knockout mice develop a systemic inflammatory syndrome with severe arthritis and autoimmunity, as well as medullary and extramedullary myeloid hyperplasia [63].…”

Therapeutic Effect of MG132 on the Aortic Oxidative Damage and Inflammatory Response in OVE26 Type 1 Diabetic Mice

“…Therefore, proteasomal inhibitors have become an attractive approach to activate Nrf2-mediated anti-oxidative pathway in the prevention of various oxidative stress-initiated diseases [5]. Among proteasome inhibitors, MG132 is specific, potent, reversible, and cell permeable and plays a key role in blocking the degradation of ubiquitin-conjugated proteins in mammalian cells by the 26S complex without affecting its ATPase or isopeptidase activities [6]. …”