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Digital archive of theses discussed at the University of Pisa


Thesis etd-09302009-105205

Thesis type
Tesi di dottorato di ricerca
Thesis title
Up-regulation of proinflammatory mediators induced by monocyte/macrophage derived microparticles in human airway epithelial cells involves an NF-κB mediated pathway, and is inhibited by peroxisome proliferator activated receptor γ-agonists
Academic discipline
Course of study
tutor Dott. Celi, Alessandro
commissario Di Bello, Vitantonio
commissario L'Abbate, Antonio
  • airway inflammation
  • cytokine
  • microparticles
  • ppar-gamma
Graduation session start date
Release date
Microparticles (MP) are phospholipid vesicles shed by cells upon activation or during apoptosis. MP range in size from 50 nm to 1 µm (Hugel et al., 2005). Evidence gathered over the past several years has demonstrated that MP are involved in numerous physiological processes, including blood coagulation and inflammation. Because of the presence of negatively charged phospholipids on the outer leaflet of MP, these structures have been long attributed a role in blood coagulation, a process that requires the assembly of multimolecular complexes on the surface of negatively charged phospholipid membranes. More recently, however, it has become evident that MP also carry other components of the parental cell besides the phospholipids, which greatly broaden the spectrum of their potential effects as intercellular mediators (Hugel et al., 2005). For example, the presence on monocyte-derived MP of tissue factor (TF), an essential cofactor for the initiation of blood coagulation (Satta et al., 1994), adds to their role in blood coagulation and thrombus formation (Celi et al., 2004). The role of leukocyte- and endothelial cell-derived MP in inflammation has also been extensively investigated. MP released by stimulated polymorphonuclear leukocytes, for example, up-regulate IL-6 and IL-8 synthesis by endothelial cells (Mesri and Altieri, 1998), while MP derived from T-lymphocytes and monocytes induce the synthesis of matrix metalloproteinases and cytokines by synovial fibroblasts (Distler et al., 2005). We have previously demonstrated that the stimulation of human monocytes/macrophages with the calcium ionophore, A23187, or with histamine, causes MP shedding, and that incubation of these MP with airway epithelial cells results in upregulation of proinflammatory mediator synthesis, including interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1), thus potentially contributing to airway inflammation (Cerri et al., 2006). However, the molecular bases of these events are not known.
Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. Three isoforms of PPAR have been identified to date: α, β/δ and γ. Originally identified for their role on lipid and glucose regulation, PPAR have more recently been implicated in the regulation of other phenomena, including inflammation (Straus and Glass, 2007). PPAR-α is expressed, among other cell types, by alveolar and bronchial epithelial cells and its activation results in downregulation of proinflammatory mediators production, at least in part through suppression of NF-κB transcriptional activity (Hetzel et al., 2003) (Arnold and Konig, 2006). Accordingly, PPAR-γ are currently being considered as potential novel therapeutic targets in Chronic Obstructive Pulmonary Disease (COPD) (Remels et al., 2008).
Here, we demonstrate that the effect of monocytes/macrophage-derived MP on airway epithelial cell inflammation is mediated through NF-κB activation and is inhibited by PPAR-γ stimulation.