Activation of microglial cells by ceruloplasmin

作者：Lee Kyung Hee; Yun Su Jin; Nam Kyong Nyon; Gho Yong Song; Lee Eunjoo H^*

来源：Brain Research, 2007, 1171: 1-8.

DOI：10.1016/j.brainres.2007.07.053

• brain inflammation
• ceruloplasmin
• cytokine
• microglia
• mitogen-activated protein kinase
• NF-kappa B
• nitric oxide

Ceruloplasmin (Cp) is the major copper transport protein in plasma and catalyzes the conversion of toxic ferrous iron to the safer ferric iron. As an acute-phase protein, Cp is induced during inflammation. It is synthesized primarily in the liver and is expressed in several other tissues, including the brain. Elevated Cp levels have been observed in the brain of patients with neurodegenerative conditions, including Alzheimer's, Parkinson's, and Huntington's diseases. However, the exact role(s) of Cp in inflammatory and neuropathological conditions remains unclear. Microglia are the prime effector cells involved in immune and inflammatory responses in the central nervous system (CNS). They are activated during pathological conditions to restore CNS homeostasis, but chronic microglial activation endangers neuronal survival. Consequently, it is important to identify the regulators of microglial activation and the underlying mechanisms. We sought to examine whether Cp might modulate microglial activation. We observed that Cp induced nitric oxide (NO) release and inducible NO synthase mRNA expression in BV2 microglial cells and rat brain microglia. Cp also increased levels of mRNAs encoding tumor necrosis factor-alpha, interleukin-1 beta, cyclooxygenase-2, and NADPH oxidase. Treatment of BV2 cells and primary microglia with Cp induced phosphorylation of p38 MAP kinase. Moreover, Cp induced nuclear factor (NF)-kappa B activation, showing a more sustained pattern than seen with bacterial lipopolysaccharide. Cp-stimulated NO induction was significantly attenuated by a p38 inhibitor, SB203580, and the NF-kappa B inhibitor SN50. Cp induced secretion of TNF-alpha and prostaglandin E(2) in primary microglial cultures. These results suggest that Cp may play an important role in neuropathological conditions by stimulating various proinflammatory and neurotoxic molecules in microglia.

• 出版日期2007-9-26