Journal
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
Volume 294, Issue 6, Pages C1436-C1442Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00489.2007
Keywords
blood-brain barrier; leukemia inhibitory factor; lipopolysaccharide; tumor necrosis factor; nuclear factor-kappa B; neuroinflammation
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Funding
- NIDDK NIH HHS [R56 DK054880, DK-54880, R01 DK054880] Funding Source: Medline
- NINDS NIH HHS [R01 NS045751-04, R01 NS046528-03, NS-46528, R01 NS046528, R01 NS045751, NS-45751] Funding Source: Medline
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Leukemia inhibitory factor (LIF) is a proinflammatory cytokine mediating a variety of central nervous system (CNS) responses to inflammatory stimuli. During lipopolysaccharide (LPS)-induced inflammation, blood concentrations of LIF increase, correlating with lethality of sepsis. Circulating LIF crosses the blood-brain barrier (BBB) by a saturable transport system. Here we determine how this transport system is regulated in neuroinflammation. Using transport assays that quantify the influx rate and volume of distribution of LIF in mice, we show that LPS facilitated the permeation of LIF from the blood to the brain without compromising the paracellular permeability of the BBB as determined by coadministration of fluorescein. Concurrently, gp130 (shared by the interleukin-6 family of cytokines), but not gp190 (the specific receptor for LIF) or cilliary neutrophic factor (CNTF-R alpha, a unique receptor for cilliary neurotrophic factor that also uses gp130 and gp190), showed increased levels of mRNA and protein expression in cerebral microvessels from the LPS-treated mice. The upregulation of gp130 by LPS was at least partially mediated by vascular tumor necrosis factor receptor (TNFR)1 and TNFR2. This was shown by elevated TNFR1 and TNFR2 mRNA and protein in cerebral microvessels after LPS and by the absence of the LPS effect on gp130 in knockout mice lacking these receptors. The results show that neuroinflammation by LPS induces endothelial signaling and enhances cytokine transport across the BBB.
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