Abstract
β-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 β-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.
- Received July 9, 2004.
- Accepted December 17, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|