The Roles of Adhesion Molecules and Matrix Metalloproteinases in IL-1beta-Induced Pulmonary Inflammation

Several factors have been shown to trigger the mechanisms for the pathologenesis of asthma and airway inflammation. It has been demonstrated that the recruitment of circulating polymorphonuclear cells (PMNs) to the airway resident cells play a pivotal role in the initiation and progression of inflammation responses. Adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) is an inducible cell surface glycoprotein on several cell types and plays an important role in several inflammatory and immune responses. Thus, up-regulation of VCAM-1 by cytokines that govern PMN adhesion to human tracheal smooth muscle cells (HTSMCs) may occur and contribute to the damage to these cells seen in inflammatory responses of asthma. Elevated levels of pro-inflammatory cytokines including interleukin-1芻(IL-1芻) in the bronchoalveolar lavage fluid have been detected in allergic asthmatic patients. IL-1芻exerts as a potent stimulus in inflammatory responses through up-regulation of many gene expressions, including adhesion molecules (i.e. VCAM-1). The expression of VCAM-1 induced by IL-1芻may be integrated to the signaling networks that augment airway inflammation by recruiting and activating leukocytes and lead to airway remodeling. Although cytokines such as IL-1芻have been reported to activate all of these mitogen-activated protein kinases (MAPKs) including p42/p44 MAPK, p38 MAPK, and the c-jun-N-terminal kinase (JNK), the relationship between the activation of these pathways and expression of adhesion molecules or other genes remain unknown. Therefore, whether activation of these MAPK pathways by IL-1芻linked to VCAM-1 expression is needed determining in HTSMCs. In addition, it is of interest that many of the genes regulated by MAPKs are dependent on NF-豈B for transcription. NF-豈B has also been shown to involve in VCAM-1 gene expression at the transcriptional level in various cell types. In addition to up-regulation of adhesion molecules leading to inflammation, degradation of extracellular matrix (ECM) by matrix metalloproteinases (MMPs) may be implicated in tissue remodeling and exaggerate of airway diseases. Recruitment and infiltration of PMNs into surrounding tissue are a multiple step process which requires changes in cell-cell contact, cell substrate interaction, and degradation of ECM by MMPs. IL-1芻has been shown to promote cell migration and infiltration in a cell type- and context-dependent manner by triggering distinct intracellular signaling cascades through up-regulation of MMPs expression in several cell types. It has been reported that T cells binding to VCAM-1 on cytokine-triggered endothelial cells activates MMP-2 in T cells and inhibition of MMP-2 with tissue inhibitor of metalloproteinase (TIMP-2) blocks VCAM-1-mediated T cell migration. This MMP activation and degradation of ECM could then cause localized retraction of the endothelial cells to allow leukocytes to migrate out of the vasculature. However, the relationship of VCAM-1 and MMP-2 as well as -9 expression and their signal transduction pathways involved in IL-1芻洶responses remain unknown. Therefore, this proposal will be focus to investigate the mechanisms underlying the intracellular signalings involved in VCAM-1 and MMP expression induced by IL-1芻洶in HTSMCs. The hypothesis of this proposal is that up-regulation of VCAM-1 and MMP-2 and -9 induced by IL-1芻 may contribute to leukocyte/HTSMCs interaction and promote inflammatory responses in airways. In addressing these questions, the experiments will be performed to investigate the roles of MAPKs, PI3-K/Akt, AP-1, and NF-豈B in IL-1芻-induced VCAM-1 and MMP mRNA and protein production in HTSMCs. These results will provide new insight into the mechanisms of IL-1芻action, supporting the hypothesis that cytokines may contribute to leukocyte/HTSMCs interaction and promote inflammatory responses involved in the development of airway diseases. Increased understanding of signal transduction mechanisms underlying VCAM-1 and MMP gene regulation will create opportunities for the development of anti-inflammation, anti-cancer and anti-metastasis therapeutic strategies.

Project ID:PC9706-0157
External Project ID:NSC95-2320-B182-047-MY3