Roles of Interleukin-17 in Endothelial Cells Endothelial cell (EC) activation and inflammation significantly contribute to vascular inflammation. In addition to being stimulated by proinflammatory/proatherogenic risk factors such as hyperlipidemia, ECs are also the target of proinflammatory cytokines. Since 2003, a new lineage of CD4+RORt+ (retinoid-related orphan receptor) T cells has been defined by its production of proinflammatory cytokine interleukin-17 (IL-17) and hence named T-helper 17 (Th17) cells. These cells are found to play an essential role in promoting autoimmune diseases and inflammation. However, an important question of whether molecular signaling pathway of IL-17 plays a critical role in EC activation remains to be answered. Therefore, the goal of this proposal is to examine a central hypothesis that IL-17, induced by hyperlipidemia, plays a critical role in EC activation. The publications from our labs and others'as well as our preliminary data support this hypothesis: (i) IL-17 receptor A (IL-17RA) is expressed in aortic ECs. High levels of IL-17 receptor C (IL-17RC) expression are observed in ECs, suggesting the functional receptor complex IL-17RA/C is expressed in ECs and is able to initiate signaling in response to IL-17 stimulation;(ii) IL-17 is upregulated in human aortic ECs exposed to disturbed blood flow, an EC activation condition, suggesting that ECs can be further stimulated by IL-17 via an autocrine mechanism;(iii) Plasma IL-17 level and Th17 cells are elevated in apolipoprotein E deficient (ApoE-/- ) atherogenic mice, suggesting that hyperlipidemia makes more IL-17 available to stimulate ECs;and (iv) Inhibition of IL-17 suppresses inflammation. Inhibition of IL-17 with antibodies attenuates vascular inflammation in ApoE-/- mice, suggesting that IL-17 plays a critical role in vascular inflammation. We have a long standing interest in studying immune regulation of endothelial activation and vascular inflammation. Therefore, we have the expertise to complete this project. This goal will be pursued through the execution of the following specific aims: (1) To determine whether IL-17 signaling pathway is upregulated in aortic ECs in ApoE-/- mice;(2) To determine whether IL-17-induced human EC activation is mechanistically dependent on its upregulation of proinflammatory cytokines and chemokines;(3) To determine whether IL-17 gene depletion inhibits EC activation in IL-17-/-/ApoE-/- mice. This project is significant since success of this project may lead to future development of new therapeutics for treating EC activation/inflammation.
There is increasing evidence that vascular endothelial cell (ECs) activation and inflammation significantly contribute to the development of vascular inflammation. However, the importance of newly characterized cytokine interleukin-17 (IL-17) signaling plays a critical role in initiating EC activation and inflammation remains poorly defined. The proposed studies will provide better understanding whether the elucidation of IL-17 molecular signaling in EC activation and inflammation can lead to the development of new therapeutics for treating vascular cell inflammation.
|Yang, Jiyeon; Fang, Pu; Yu, Daohai et al. (2016) Chronic Kidney Disease Induces Inflammatory CD40+ Monocyte Differentiation via Homocysteine Elevation and DNA Hypomethylation. Circ Res 119:1226-1241|
|Liu, Suxuan; Xiong, Xinyu; Thomas, Sam Varghese et al. (2016) Analysis for Carom complex, signaling and function by database mining. Front Biosci (Landmark Ed) 21:856-72|
|Ferrer, Lucas M; Monroy, Alexandra M; Lopez-Pastrana, Jahaira et al. (2016) Caspase-1 Plays a Critical Role in Accelerating Chronic Kidney Disease-Promoted Neointimal Hyperplasia in the Carotid Artery. J Cardiovasc Transl Res 9:135-44|
|Wang, Xin; Li, Ya-Feng; Nanayakkara, Gayani et al. (2016) Lysophospholipid Receptors, as Novel Conditional Danger Receptors and Homeostatic Receptors Modulate Inflammation-Novel Paradigm and Therapeutic Potential. J Cardiovasc Transl Res 9:343-59|
|Xi, Hang; Zhang, Yuling; Xu, Yanjie et al. (2016) Caspase-1 Inflammasome Activation Mediates Homocysteine-Induced Pyrop-Apoptosis in Endothelial Cells. Circ Res 118:1525-39|
|Shao, Ying; Chernaya, Valeria; Johnson, Candice et al. (2016) Metabolic Diseases Downregulate the Majority of Histone Modification Enzymes, Making a Few Upregulated Enzymes Novel Therapeutic Targets--"Sand Out and Gold Stays". J Cardiovasc Transl Res 9:49-66|
|Li, Xinyuan; Fang, Pu; Li, Yafeng et al. (2016) Mitochondrial Reactive Oxygen Species Mediate Lysophosphatidylcholine-Induced Endothelial Cell Activation. Arterioscler Thromb Vasc Biol 36:1090-100|
|Li, Xinyuan; Fang, Pu; Yang, William Y et al. (2016) Mitochondrial ROS, uncoupled from ATP synthesis, determine endothelial activation for both physiological recruitment of patrolling cells and pathological recruitment of inflammatory cells. Can J Physiol Pharmacol :1-6|
|Mai, Jietang; Nanayakkara, Gayani; Lopez-Pastrana, Jahaira et al. (2016) Interleukin-17A Promotes Aortic Endothelial Cell Activation via Transcriptionally and Post-translationally Activating p38 Mitogen-activated Protein Kinase (MAPK) Pathway. J Biol Chem 291:4939-54|
|Li, Ya-Feng; Li, Rong-Shan; Samuel, Sonia B et al. (2016) Lysophospholipids and their G protein-coupled receptors in atherosclerosis. Front Biosci (Landmark Ed) 21:70-88|
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