sICAM-1 and TNF-α induce MIP-2 with distinct kinetics in astrocytes and brain microvascular endothelial cells

The dysfunction of the blood‐brain barrier (BBB) occurring after traumatic brain injury (TBI) is mediated by intracerebral neutrophil accumulation, chemokine release (e.g., interleukin (IL)‐8) and upregulation of adhesion molecules (e.g., intercellular adhesion molecule (ICAM)‐1). In patients with severe TBI, we previously found that elevated cerebrospinal fluid (CSF) IL‐8 and soluble (s)ICAM‐1 correlate with BBB dysfunction, and this prompted us to concomitantly monitor IL‐8, sICAM‐1 and their stimulator tumor necrosis factor (TNF)‐α in CSF. Potential mechanisms for upregulation of the IL‐8 analogue, murine macrophage inflammatory protein (MIP)‐2, and sICAM‐1 at the BBB were studied using cultured mouse astrocytes and brain microvascular endothelial cells (MVEC). In CSF of seven patients, IL‐8 and sICAM‐1 were elevated for 19 days after severe TBI, whereas TNF‐α exceeded normal values on 9 days. Stimulation of MVEC and astrocytes with TNF‐α simultaneously induced the release of MIP‐2 reaching saturation by 4–8 hr and of sICAM‐1 increasing continuously from 2–4 hr to 12 hr. Augmented sICAM‐1 production correlated with enhanced membrane‐bound (m)ICAM‐1 expression in both cell types (rs = 0.96 and 0.90, P < 0.0001), but was markedly higher in astrocytes. The release of sICAM‐1 was not influenced by IL‐8 or MIP‐2, although astrocytes and MVEC expressed the IL‐8/MIP‐2 receptor (CXCR‐2) as determined by FACS analysis. Instead, we found that sICAM‐1 strongly induced MIP‐2 secretion by both cell types with kinetics differing from those evoked by TNF‐α. If added together, sICAM‐1 and TNF‐α synergistically induced MIP‐2 production suggesting the involvement of two different pathways for MIP‐2 regulation. J. Neurosci. Res. 60:733–742, 2000. © 2000 Wiley‐Liss, Inc.