The Role of Nuclear Factor-Kappa B in Fibrinogen-Induced Inflammatory Responses in Cultured Primary Neurons

Abstract

Traumatic brain injury (TBI) is an inflammatory disease associated with a compromised blood–brain barrier (BBB) and neurodegeneration. One of the consequences of inflammation is an elevated blood level of fibrinogen (Fg), a protein that is mainly produced in the liver. The inflammation-induced changes in the BBB result in Fg extravasation into the brain parenchyma, creating the possibility of its contact with neurons. We have previously shown that interactions of Fg with the neuronal intercellular adhesion molecule-1 and cellular prion protein induced the upregulation of pro-inflammatory cytokines, oxidative damage, increased apoptosis, and cell death. However, the transcription pathway involved in this process was not defined. The association of Fg with the activation of the nuclear factor-κB (NF-κB) and the resultant expression of interleukin-6 (IL-6) and C–C chemokine ligand-2 (CCL2) were studied in cultured primary mouse brain cortex neurons. Fg-induced gene expression of CCL2 and IL-6 and the expression of NF-κB protein were increased in response to a specific interaction of Fg with neurons. These data suggest that TBI-induced neurodegeneration can involve the direct interaction of extravasated Fg with neurons, resulting in the overexpression of pro-inflammatory cytokines through the activation of transcription factor NF-κB. This may be a mechanism involved in vascular cognitive impairment during neuroinflammatory diseases.