title: Upregulation of phagocyte-like NADPH oxidase by cytokines in pancreatic beta-cells: attenuation of oxidative and nitrosative stress by 2-bromopalmitate.
abstract: Phagocyte-like NADPH oxidase (Nox2) has been shown to play regulatory roles in the metabolic dysfunction of the islet β-cell under the duress of glucolipotoxic conditions and exposure to proinflammatory cytokines. However, the precise mechanisms underlying Nox2 activation by these stimuli remain less understood. To this end, we report a time-dependent phosphorylation of p47phox, a cytosolic subunit of Nox2, by cytomix (IL-1β+TNFα+IFNγ) in insulin-secreting INS-1 832/13 cells. Furthermore, cytomix induced the expression of gp91phox, a membrane component of Nox2. 2-Bromopalmitate (2-BP), a known inhibitor of protein palmitoylation, markedly attenuated cytokine-induced, Nox2-mediated reactive oxygen species (ROS) generation and inducible nitric oxide synthase (iNOS)-mediated nitric oxide (NO) generation. However, 2-BP failed to exert any significant effects on cytomix-induced CHOP expression, a marker for endoplasmic reticulum stress. Together, our findings identify palmitoyltransferase as a target for inhibition of cytomix-induced oxidative (ROS generation) and nitrosative (NO generation) stress in the pancreatic β-cell.
authors.affiliation: Beta-Cell Biochemistry Laboratory, John D. Dingell VA Medical Center, and Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Abiy M
authors.initials: AM
authors.lastname: Mohammed
authors.forename: Khadija
authors.initials: K
authors.lastname: Syeda
authors.forename: Timothy
authors.initials: T
authors.lastname: Hadden
authors.forename: Anjaneyulu
authors.initials: A
authors.lastname: Kowluru
mesh_terms: D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D054878:Lipoylation; D008562:Membrane Glycoproteins / Q000378:metabolism*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis*; D010168:Palmitates / Q000494:pharmacology*; D010766:Phosphorylation; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D051742:Transcription Factor CHOP / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D016207:Cytokines; C497251:Ddit3 protein, rat; D053583:Interleukin-1beta; D008562:Membrane Glycoproteins; D010168:Palmitates; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D051742:Transcription Factor CHOP; C022776:2-bromopalmitate; D009569:Nitric Oxide; D007371:Interferon-gamma; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1