Group VIB Phospholipase A2Promotes Proliferation of INS-1 Insulinoma Cells and Attenuates Lipid Peroxidation and Apoptosis Induced by Inflammatory Cytokines and Oxidant Agents

Abstract

Group VIB Phospholipase A2(iPLA2γ) is distributed in membranous organelles in whichβ-oxidation occurs, that is, mitochondria and peroxisomes, and is expressed by insulin-secreting pancreatic isletβ-cells and INS-1 insulinoma cells, which can be injured by inflammatory cytokines, for example, IL-1βand IFN-γ, and by oxidants, for example, streptozotocin (STZ) or t-butyl-hydroperoxide (TBHP), via processes pertinent to mechanisms ofβ-cell loss in types 1 and 2 diabetes mellitus. We find that incubating INS-1 cells with IL-1βand IFN-γ, with STZ, or with TBHP causes increased expression of iPLA2γmRNA and protein. We prepared INS-1 knockdown (KD) cell lines with reduced iPLA2γexpression, and they proliferate more slowly than control INS-1 cells and undergo increased membrane peroxidation in response to cytokines or oxidants. Accumulation of oxidized phospholipid molecular species in STZ-treated INS-1 cells was demonstrated by LC/MS/MS scanning, and the levels in iPLA2γ-KD cells exceeded those in control cells. iPLA2γ-KD INS-1 cells also exhibited higher levels of apoptosis than control cells when incubated with STZ or with IL-1βand IFN-γ. These findings suggest that iPLA2γpromotesβ-cell proliferation and that its expression is increased during inflammation or oxidative stress as a mechanism to mitigate membrane injury that may enhanceβ-cell survival.