title: sICAM-1 and TNF-alpha induce MIP-2 with distinct kinetics in astrocytes and brain microvascular endothelial cells.
abstract: 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)-alpha 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-alpha exceeded normal values on 9 days. Stimulation of MVEC and astrocytes with TNF-alpha 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 (r(s) = 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-alpha. If added together, sICAM-1 and TNF-alpha synergistically induced MIP-2 production suggesting the involvement of two different pathways for MIP-2 regulation.
authors.affiliation: Division of Research, Department of Surgery, University Hospital Zurich, Zurich, Switzerland. vivanne.otto@chi.usz.ch
authors.forename: V I
authors.initials: VI
authors.lastname: Otto
authors.forename: U E
authors.initials: UE
authors.lastname: Heinzel-Pleines
authors.forename: S M
authors.initials: SM
authors.lastname: Gloor
authors.forename: O
authors.initials: O
authors.lastname: Trentz
authors.forename: T
authors.initials: T
authors.lastname: Kossmann
authors.forename: M C
authors.initials: MC
authors.lastname: Morganti-Kossmann
mesh_terms: D000328:Adult; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001930:Brain Injuries / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D054426:Chemokine CXCL2; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008833:Microcirculation / Q000187:drug effects; D008875:Middle Aged; D015846:Monokines / Q000378:metabolism* / Q000502:physiology; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D054426:Chemokine CXCL2; D015846:Monokines; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1