MMPs contribute to TNF-alpha-induced alteration of the blood-cerebrospinal fluid barrier in vitro

Zeni P, Doepker E, Schulze-Topphoff U, Huewel S, Tenenbaum T, Galla HJ

Abstract

The epithelial cells of the choroid plexus separate the central nervous system from the blood forming the blood-cerebrospinal fluid (CSF) barrier. The choroid plexus is the main source of CSF, whose composition is markedly changed during pathological disorders, for example regarding matrix metalloproteases (MMPs) and tissue inhibitors of matrix metalloproteases (TIMPs). In the present study, we analyzed the impact of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) on the blood-CSF barrier using an in vitro model based on porcine choroid plexus epithelial cells (PCPEC). TNF-alpha evoked distinct inflammatory processes as shown by mRNA upregulation of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1. The cytokine caused a drastic decrease in transepithelial electrical resistance within several hours representing an enhanced permeability of PCPEC monolayers. In addition, the distribution of tight junction proteins was altered. Moreover, MMP activity in PCPEC supernatants was significantly increased by TNF-alpha, presumably due to a diminished expression of TIMP-3 that was similarly observed. MMP-2, -3, and -9 as well as TIMP-1 and -2 were also analyzed and found to be differentially regulated by the cytokine. The TNF-alpha-induced breakdown of the blood-CSF barrier could partially be blocked by the MMP inhibitor GM-6001. Our results show a contribution of MMPs to the inflammatory breakdown of the blood-CSF barrier in vitro. Thus TNF-alpha may mediate the binding of leukocytes to cellular adhesion molecules and the transmigration across the blood-CSF barrier.