Neuroinflammation facilitates LIF entry into brain: role of TNF.
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-Ralpha, 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.
Pan
Weihong
W
Blood-Brain Barrier Group, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA. weihong.pan@pbrc.edu
Yu
Chuanhui
C
Hsuchou
Hung
H
Zhang
Yan
Y
Kastin
Abba J
AJ
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002199:Capillary Permeability; D053739:Ciliary Neurotrophic Factor Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D019793:Fluorescein / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000097:blood / Q000378:metabolism*; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008833:Microcirculation / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D053606:Receptors, OSM-LIF / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism; D018805:Sepsis / Q000139:chemically induced / Q000378:metabolism*; D013997:Time Factors; D048069:Tumor Necrosis Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D053739:Ciliary Neurotrophic Factor Receptor alpha Subunit; D005456:Fluorescent Dyes; C494200:Il6st protein, mouse; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D053606:Receptors, OSM-LIF; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D048069:Tumor Necrosis Factors; D050822:Cytokine Receptor gp130; D019793:Fluorescein