Inflammatory genes, transcriptional regulators

PPAR is a nuclear receptor-transcription factor and is ligand-dependent and expressed in several tissues. It is initially involved in adipocyte differentiation and fatty acid synthesis. Fatty acid and eicosanoids bind to PPAR and regulate transcription. PPAR activation inhibits monocyte differentiation and expression of several pro-inflammatory genes such as iNOS, TNF, etc. PPAR activation inhibits tumor cell proliferation (epithelial, colon, prostate). PPAR is involved in angiogenesis. 

Recently, NADPH oxidase has been identified as the ROS-producing molecule in activated glial cells (Pawate et al., 2004). Cytokine stimulation of astrocytes leads to rapid activation of NADPH oxidase and release of ROS followed by expression of pro-inflammatory products like, iNOS. Consistently, attenuated expression of iNOS is observed in primary astrocytes derived from gp9F -deficient mice (Pawate et al., 2004). ROS are believed to regulate expression of pro-inflammatory gene products via NF-kB. However, the involvement of other transcription factors in ROS-mediated gliosis cannot be ruled out. 

Statins, used predominantly in the treatment of hypercholesterolemia, act by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which regulates the synthesis of cholesterol. Statins are also agonists of peroxisome proliferator activated receptors (PPARs), which are part of the nuclear receptor superfamily and when activated, can suppress transcription of pro-inflammatory genes (Chinetti et al., 2000). In vitro and in vivo studies have shown that a decrease in serum cholesterol inhibits the production of beta amyloid and plaque (Simons et al., 1998 Fassbender et al.,... 

In summary, GSH regulates the critical balance between the induction of pro-inflammatory mediators and antioxidant genes, hence it can be considered as a very important modulator of the inflammatory process. Despite this extremely important function, the regulation of the levels of GSH in response to free radical production and oxidative stress at the site of inflammation is poorly known. Knowledge of the mechanisms of redox GSH regulation and gene transcription in inflammation could lead to the development of novel therapies based on the pharmacological manipulation of the production of this important antioxidant in inflammation and injury. 

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