Regulation of macrophage and preadipocyte proliferation and migration by C1P

Abstract

Chronic inflammatory diseases are the most significant cause of death in the world. Indeed, according to the World Health Organization (WHO), 3 out of 5 people die due to chronic inflammatory diseases such as stroke, chronic respiratory diseases, heart disorders, cancer, obesity or diabetes. It has been demonstrated that sphingolipid metabolism is altered in this type of disorders. Therefore, understanding the molecular mechanisms by which bioactive sphingolipids participate in the establishment or progression of those diseases may be useful for developing novel therapeutic strategies to control them. In the first chapter of this thesis, we demonstrate that the bioactive sphingolipid ceramide 1-phosphate (C1P) induces survival, proliferation and migration of preadipocytes through mechanisms that implicate the PI3K/Akt, MEK/ERK1-2 and JAK/STAT3 signaling pathways. These biological actions suggest a possible role of this phosphosphingolipid in fat accumulation and dysfunction of adipose tissue, which might lead to metabolic diseases, most notably, obesity. In the second chapter we show that exogenous C1P inhibits alveolar macrophage migration, an action that seems to be caused by dephosphorylation of important proteins that are involved in the regulation of cell migration, such as, PKB/Akt, ERK1-2, PAK1 and Paxillin. In addition, the latter study provides evidence that granular nanosized silica (SiO2)-conditioned medium enhances alveolar macrophage migration through activation of PI3K/Akt signaling cascade and that C1P inhibits this action by blocking PKB/Akt phosphorylation. Taken together, the results of this thesis support the notion that C1P may have anti-inflammatory properties in lung cells.