Macrophage inflammatory protein 2 inhibits beta-amyloid peptide (1-42)-mediated hippocampal neuronal apoptosis through activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling pathways.
beta-Amyloid peptide accumulation in senile plaques in the brains of patients with Alzheimer's disease has been considered as a major cause of neuronal death. The present study demonstrated that the CXCR2 ligands macrophage inflammatory protein 2 (MIP-2), CXCL1, and CXCL8, protected hippocampal neurons against beta-amyloid (1-42) induced death. MIP-2-activated extracellular signal-regulated kinase (ERK)1/2 and Akt and both the mitogen-activated protein kinase kinase 1 (MEK1) and phosphatidylinositol 3-kinase (PI3K) inhibitors 2'-amino-3'-methoxyflavone (PD98059) and wortmannin reduced the neuroprotective effect of MIP-2. MIP-2 induced weak phosphorylation of ribosomal S6 kinase (RSK) 1 but remarkable phosphorylation and nuclear translocation of RSK2. MIP-2-induced phosphorylation of RSK2 was inhibited by PD98059 but not by wortmannin. MIP-2 treatment of the neuronal cells resulted in phosphorylation of Bad at both the Ser-112 and Ser-136. The phosphorylation at Ser-112 was blocked by PD98059, whereas the phosphorylation at Ser-136 was blocked by wortmannin. The transcription factor cyclic AMP response element binding protein (CREB) was phosphorylated by MIP-2 stimulation of the neuronal cells. MIP-2-induced CREB phosphorylation was reduced by both PD98059 and wortmannin. These data demonstrate that both MEK1-ERK1/2 and PI3K-Akt signaling pathways are involved in CXCR2-mediated neuroprotection and that multiple downstream signaling events, including RSKs, Bad, and CREB, are activated in this process.
Watson
Kurt
K
Department of Pharmacology, Meharry Medical College, 1005 Dr. DB Todd Jr. Blvd., Nashville, TN 37208, USA.
Fan
Guo-Huang
GH
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors*; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D054426:Chemokine CXCL2; D018925:Chemokines / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology* / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors*; D019869:Phosphatidylinositol 3-Kinases; D015398:Signal Transduction; D000077191:Wortmannin
D016229:Amyloid beta-Peptides; D000730:Androstadienes; D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D004791:Enzyme Inhibitors; D005419:Flavonoids; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D019869:Phosphatidylinositol 3-Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000077191:Wortmannin