Macrophage-Colony-Stimulating Factor-Induced Activation of Extracellular-Regulated Kinase Involves Phosphatidylinositol 3-Kinase and Reactive Oxygen Species in Human Monocytes

Abstract

We previously reported that activation of the phosphatidylinositol (PI) 3-kinase pathway was important in M-CSF-induced monocyte survival. Because M-CSF also induces activation of the mitogen-activated protein (MAP) kinase extracellular-regulated kinase (Erk), we focused on dissecting the mechanism used by M-CSF to induce Erk activation in human monocytes. We found that, in addition to the MAP/Erk kinase inhibitor PD098059, the PI 3-kinase inhibitors LY294002 and wortmannin both suppressed Erk activation in M-CSF-treated monocytes, suggesting that 3-phosphorylated products of PI 3-kinase played a role in Erk activation. Investigating the biochemical pathways regulated by PI 3-kinase to activate Erk, we found that, in response to M-CSF, normal human monocytes induced reactive oxygen species (ROS), which were suppressed by the PI 3-kinase inhibitor wortmannin but not by the solvent control DMSO or the MAP/Erk kinase inhibitor PD098059. We next found that, in the absence of M-CSF, ROS could induce Erk activation in human monocytes. Exogenous H2O2 induced Erk activation in human monocytes, which was suppressed by exogenous catalase. To determine whether ROS induced by M-CSF played a role in Erk activation, we found that N-acetylcysteine and diphenyleneiodonium both suppressed Erk activation in M-CSF-treated monocytes. Erk activation by M-CSF also seemed to play a role in cellular survival in monocytes. These data suggest that, in M-CSF-stimulated human monocytes, PI 3-kinase products and ROS production play a role in Erk activation and monocyte survival.

Presentation of Nitric Oxide Regulates Monocyte Survival through Effects on Caspase-9 and Caspase-3 Activation

“…We previously described that M-CSF stimulation augments the production of reactive oxygen species by human monocytes (15). We speculated that PAPA NONOate and DEA NONOate promote caspase-9 and caspase-3 activation by reducing tyrosine phosphorylation events in monocytes stimulated with M-CSF.…”

“…Peroxynitrite can nitrate tyrosine residues and inhibit tyrosine phosphorylationmediated activation events. The monocyte survival factor macrophage colony-stimulating factor (M-CSF) induces reactive oxygen species production (15) and relies on the phosphorylation of tyrosine residues in the cytoplasmic domain of the receptor to activate signaling pathways. We speculated that nitric oxide donors (such as 1-propamine 3-(2-hydroxy-2-nitroso-1-propylhydrazine) (PAPA) NONOate and diethylamine (DEA) NONOate) that do not target thiol residues would interrupt phosphorylation of these tyrosine residues and reduce monocyte survival induced by M-CSF.…”

Comparative Study of Toxic Effects of Anatase and Rutile Type Nanosized Titanium Dioxide Particles in vivo and in vitro

“…However, activation of alveolar macrophages is strongly associated with inflammatory reactions and ROS production (Renwick et al, 2001;Bhatt et al, 2002;Wang et al, 2007). Also, MIP1a, secreted from rnTiO 2 burden alveolar macrophages, is possibly involved in the promotion of lung carcinogenesis (Xu et al, 2010).…”

N-(4-Hydroxyphenyl)retinamide-induced apoptosis triggered by reactive oxygen species is mediated by activation of MAPKs in head and neck squamous carcinoma cells

“…The proapoptotic role of ERK in 4HPR-induced cell death is a novel finding that is somewhat unexpected because ERK has been associated with enhanced cell proliferation (Chang and Karin, 2001) and increased survival signal that counteracted proapoptotic effects mediated by JNK and/or p38 activation (Xia et al, 1995;Seidman et al, 2001;Carvalho et al, 2004;Yu et al, 2004). Furthermore, oxidative stress has been shown to activate ERK as a protective mechanism (Guyton et al, 1996;Aikawa et al, 1997;Bhatt et al, 2002). However, a proapoptotic role has been demonstrated for ERK in several studies with different stimuli, including anticancer drugs (Stanciu et al, 2000;Wang et al, 2000;Guise et al, 2001;Xiao and Singh, 2002;Lee et al, 2003;Zhang et al, 2003;Nguyen et al, 2004).…”