The infiltration and accumulation of monocytes/macrophages is a characteristic feature seen in a number of chronic inflammatory disease states such as atherosclerosis. With respect to latter, activated macrophages have been identified in every phase of the atherosclerotic lesions development-from earliest lesion termed the fatty streak to the mature and obstructive plaque. Therefore, identification of the molecular mechanisms regulating macrophage activation is of considerable scientific and therapeutic interest. ? ? The Kruppel-like Factor 2 (KLF2) is a zinc-finger transcription factor implicated in endothelial cell pro-inflammatory activation and T cell quiescence. Studies comparing the in vivo transcriptomes of monocytes purified from patients undergoing carotid endarterectomy and normal subjects by using the serial analysis of gene expression technique revealed that (1) KLF2 is expressed in human monocytes and (2) that expression is reduced in patients with coronary artery disease. Consistent with this observation, in vitro studies confirm that KLF2 expression in primary human monocytes and monocytic cell lines is reduced with activation. Adenoviral overexpression of KLF2 inhibits the lipopolysaccharide (LPS)-mediated induction of pro- inflammatory factors, cytokines, and chemokines. Conversely, siRNA mediated knockdown of KLF2 enhances pro-inflammatory gene expression. Finally, reconstitution of immunodeficient mice with KLF2 overexpressing monocytes significantly reduced carrageenan-induced acute paw inflammation and edema. Mechanistically, our studies indicate that KLF2 inhibits the key pro-inflammatory regulator NF-kB. On the basis of these observations, we hypothesize that KLF2 may serve as a negative regulator of monocyte/macrophage activation. The studies outlined in this proposal will (1) examine the effect of KLF2 overexpression and deficiency on monocyte/macrophage functions in vitro, (2) explore the molecular basis for KLF2's ability to inhibit key pro-inflammatory pathways, and (3) explore the effect of KLF2 overexpression on acute and chronic models of inflammation. The results of these investigations will provide considerable insight regarding the role of KLF2 as a regulator of macrophage activation. Furthermore, these results may provide a foundation for novel strategies to limit macrophage activation and inflammation. ? ? ?
| Sweet, David R; Fan, Liyan; Hsieh, Paishiun N et al. (2018) Krüppel-Like Factors in Vascular Inflammation: Mechanistic Insights and Therapeutic Potential. Front Cardiovasc Med 5:6 |
| Lu, Yuan; Fujioka, Hisashi; Joshi, Dinesh et al. (2018) Mitophagy is required for brown adipose tissue mitochondrial homeostasis during cold challenge. Sci Rep 8:8251 |
| Fan, Liyan; Hsieh, Paishiun N; Sweet, David R et al. (2018) Krüppel-like factor 15: Regulator of BCAA metabolism and circadian protein rhythmicity. Pharmacol Res 130:123-126 |
| Hsu, Kuo-Sheng; Zhao, Xuan; Cheng, Xiwen et al. (2017) Dual regulation of Stat1 and Stat3 by the tumor suppressor protein PML contributes to interferon ?-mediated inhibition of angiogenesis. J Biol Chem 292:10048-10060 |
| Sangwung, Panjamaporn; Zhou, Guangjin; Nayak, Lalitha et al. (2017) KLF2 and KLF4 control endothelial identity and vascular integrity. JCI Insight 2:e91700 |
| Shen, Yuyan; Hong, Hong; Sangwung, Panjamaporn et al. (2017) Kruppel-like factor 4 regulates neutrophil activation. Blood Adv 1:662-668 |
| Sangwung, Panjamaporn; Zhou, Guangjin; Lu, Yuan et al. (2017) Regulation of endothelial hemoglobin alpha expression by Kruppel-like factors. Vasc Med 22:363-369 |
| Thomas, Graham D; Hanna, Richard N; Vasudevan, Neelakatan T et al. (2016) Deleting an Nr4a1 Super-Enhancer Subdomain Ablates Ly6Clow Monocytes while Preserving Macrophage Gene Function. Immunity 45:975-987 |
| Sun, Haipeng; Olson, Kristine C; Gao, Chen et al. (2016) Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure. Circulation 133:2038-49 |
| Prosdocimo, Domenick A; Sabeh, M Khaled; Jain, Mukesh K (2015) Kruppel-like factors in muscle health and disease. Trends Cardiovasc Med 25:278-87 |
Showing the most recent 10 out of 48 publications
