Mechanisms of Sphingosine 1-Phosphate Induced Intercellular Adhesion Molecule-1 Expression in Human Pulmonary Alveolar Epithelial Cells

Human pulmonary alveolar epithelial cells (HPAEpiCs) play an important role in the proliferation, migration, and inflammatory processes in the respiratory system. Several factors have been implicated to trigger the mechanisms for the pathologenesis of airway diseases including asthma and chronic obstructive pulmonary disease (COPD) characterized by inflammatory processes. Several studies demonstrate that expression of adhesive molecules on the cell surface of endothelial cells plays a critical role in these inflammatory responses. Although the factors concerning about the increased incidence of inflammatory responses are well known, however, the intracellular signaling pathways involved in the expression of inflammatory proteins are not completely defined. Sphingosine 1-phosphate (S1P), one of the lipid components has attracted much attention as a possible signaling mediator that regulates immune responses and inflammatory processes in the respiratory system. Although S1P has been shown to activate MAPKs, PI3K/Akt, receptor tyrosine kinases (RTK) and other signaling molecules and up-regulation of inflammatory target proteins such as intercellular adhesion molecule (ICAM)-1 in various cell types, however, the mechanisms underlying S1P-induced ICAM-1 expression in HPAEpiCs remain unknown. Thus, this proposal is to investigate the intracellular signaling pathways implicated in S1P-induced ICAM-1 expression in these cells. Our hypothesis is that up-regulation of ICAM-1 induced by S1P may contribute to inflammatory responses or exert as a host defense in respiratory diseases. To address these questions, the experiments will be performed to investigate the roles of GPCRs, ROS, MAPKs, RTK, PI3K/Akt, Ca2+/PKC, NF-B, activator protein-1 (AP-1), and Sp1 in S1P-induced ICAM-1 expression in HPAEpiCs. These results will provide new insight into the mechanisms of S1P action, supporting the hypothesis that S1P may contribute to inflammatory responses involved in the development of respiratory diseases. Increased understanding of signal transduction mechanisms underlying ICAM-1 gene regulation will create opportunities for the development of anti-inflammation therapeutic strategies.

Project ID:PC10408-2128
External Project ID:MOST104-2320-B182-010