Pro-inflammatory signaling pathways

Figure 15.3 Resveratrol modulation of pro-inflammatory signaling pathways. Resver-atrol represses transcriptional activation of various pro-inflammatory genes by inhibiting pro-inflammatory stimuli-induced activation of upstream kinases, such as MAP kinases, PI3K/Akt, IKK, PKC, etc., and blocking the DNA binding of eukaryotic transcription factors, such as NF-kB, AP-1, and STAT3.

Kundu JK, Shin YK, Surh Y-J. 2006b. Resveratrol modulates phorbol ester-induced pro-inflammatory signal transduction pathways in mouse skin in vivo NF-kappaB and AP-1 as prime targets. Biochem Pharmacol 72 1506-1515. 

A3 receptors are present on human eosinophils and couple to signalling pathways that lead to cell activation ( Kohno et al. 1996a Reeves et al. 2000). Despite this it has not proven easy to demonstrate the functional consequences of activation of these sites (Reeves et al. 2000). Nevertheless, the chronic inflammation in asthma is characterised by extensive infiltration of the airways by activated eosinophils (Holgate 1999 Pearlman 1999) and it remains possible that the elevated adenosine concentrations associated with asthma would contribute to eosinophil activation through stimulation of A3 receptors. In addition, it has been speculated that activation of A3 receptors may protect eosinophils from apoptosis (Gao et al. 2001). Thus, blockade of A3 receptors may reduce the numbers of eosinophils and their activation thereby reducing the pro-inflammatory burden in the lung. Consistent with this, following 6 weeks treatment of mild asthmatics with theophylline there was a... 

All identified TLRs are type I transmembrane proteins, whose intracellular domains contain regions homologous to the intracellular domains of IL-1R and are referred to as TIR domains (Takeda et ah, 2003). These intracellular domains are able to trigger signalling pathways known to activate the nuclear factor kappa B (NF-kB) (Medzhitov et ah, 1998 O Neill, 2000), which in turn leads to the secretion of pro-inflammatory cytokines such as TNF-a, IL-6 and IL-8. The membrane distribution of TLRs as well as their intracellular trafficking has only now beginning... 

The failure of antioxidant mechanisms to correct redox disequilibrium could lead to the escalation of oxidative to tier 2. Tier 2 cellular responses are characterized by the activation of cellular signaling pathway such as stress-activated kinases (p38 MAP kinase and JNK) along with activation and nuclear translocation of transcription factors NF-kB and STAT-1. NF-KB-induced transcriptional activation leads to the production of a number of pro-inflammatory cytokines, including the neutrophil chemoattractant IL-8. STAT-1 activation stimulates the increased production of CXC-motif chemokines that function in lymphocyte recruitment and activation. Therefore, tier 2 oxidative responses result in an inflammatory response in the lung. 

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