The Pharmacological Effects of Flavonoids on Cytokine-Induced Expression of Inflammatory Proteins in Airway Resident Cells

Elevated levels of pro-inflammatory cytokines including tumor necrosis factor-(TNF-) and interleukin-1 (IL-1) in the bronchoalveolar lavage fluid have been detected in allergic asthmatic patients. Cytokines exert as potent stimuli in inflammatory responses through up-regulation of many gene expressions, including cytokines, chemokines, proteases, receptor proteins, cyclooxygenase and adhesion molecules. Recently, the expression of these target proteins induced by cytokines may be integrated to the signaling networks that augment airway inflammation by recruiting and activating leukocytes and lead to airway remodeling. In our previous studies, TNF-and IL-1have been reported to activate all of these mitogen-activated protein kinases (MAPKs) including p42/p44 MAPK, p38 MAPK, and JNK, PI3K/Akt, transactivation of growth factor receptor, and NF-B in tracheal smooth muscle cells and A549 cells. Activation of these signaling pathways leads to the expression of inflammatory proteins such as adhesion molecules, COX-2, cPLA2, and matrix metalloproteinase (MMP)-9 in these cells. All of these components have been shown to be implicated in airway inflammation. Although the pathogenesis of inflammatory processes has been extensively approached, there is no effective treatment available in the clinical therapeutics. Therefore, this proposal will be focus to develop and evaluate the potency of Chinese herbal medicines on the expression of inflammatory proteins including COX-2, adhesion molecules, cytosolic phospholipase A2 (cPLA2), and MMP-9 in human airway epithelial cells and tracheal smooth muscle cells. Flavonoids have been suggested to exert human health benefits by anti-oxidant and anti-inflammatory mechanisms. Flavonoids also have inhibitory effects on several protein tyrosine and serine/threonine kinases, including PI3-K/Akt, AMP-activated kinase, protein kinase C, epidermal growth factor receptor tyrosine kinase, and I B kinase in various cell types. All of these protein kinases are engaged in the expression of inflammatory proteins induced by cytokines. The potently inhibitory effects of flavonoid compounds on these enzymes reflect themselves could be potential candidates for the development of anti-inflammation therapeutic strategy. In this study, we will investigate whether and by what mechanisms dietary flavonoids inhibit expression of COX-2, cPLA2, ICAM-1, VCAM-1, and MMP-9 in human airway epithelial cells and tracheal smooth muscle cells, which are relevant to airway inflammation. Therefore, the long-term goal of this proposal will investigate whether and by what mechanisms dietary flavonoids inhibit expression of COX-2, cPLA2, ICAM-1, VCAM-1, and MMP-9 in human airway epithelial cells and tracheal smooth muscle cells, which are relevant to airway inflammation. The present study will be undertaken to determine whether the inhibitory abilities of flavonoid compounds in activation of PI3-K/Akt, transactivation of EGFR and PDGFR as well as translocation of NF-B and to investigate their roles in the activation of these signaling pathways for TNF--induced responses in HTSMCs and A549 cells. The expression of transcription factors including c-fos, c-jun, NF-B, AP-1, histone acetylation/deacetylation, and p300 regulated by TNF- will be also investigated in the presence of  these compounds. Therefore, in this work we will investigate the mechanisms flavonoids attenuate the expression of inflammatory proteins induced by TNF-mediated through p42/p44 MAPK, p38 MAPK, and JNK, PI3K/Akt, transactivation of growth factor receptor, and NF-B in tracheal smooth muscle cells and A549 cells. In particular, we will characterize: 1. The efficacies of different flavonoids on the expression of COX-2, cPLA2, ICAM-1, VCAM-1, and MMP-9 induced by TNF-. 2. The potencies of different flavonoids on the MAPKs phosphorylation stimulated by TNF-. 3. The efficacies of different flavonoids on the transactivation of growth factor receptors stimulated by TNF- 4. The potencies of different flavonoids on the PI3K/Akt phosphorylation stimulated by TNF- 5. The effects of different flavonoids on the NF-B activation stimulated by TNF-. 6. The molecular mechanisms of anti-inflammation by different flavonoids interrupted the up-stream and down-stream components in MAPKs, PI3K/Akt, transactivation of growth factor receptors, and NF-B pathways. The effects of different flavonoids on expression of transcription factors induced by TNF-

Project ID:PC9709-0199
External Project ID:NSC97-2320-B182-008