Opposing effects of proteasomes and lysosomes on LIFR: Modulation by TNF

Yu, Cong; Kastin, Abba J.; Tu, Hong; Pan, Weihong

doi:10.1007/s12031-007-0017-4

Cited by 22 publications

(27 citation statements)

References 37 publications

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“…This in vivo observation differs from our in vitro results in RBE4 cerebral microvessel endothelial cells, in which binding and endocytosis of LIF were reduced after TNF treatment accompanied by decreased LIFR and increased gp130 (40,41). Since the cell studies involved stimulation with TNF, rather than LPS, and a shorter duration of treatment than received by the mice, the discrepancy probably reflects the complexity of dynamic changes in vivo.…”

Section: Discussioncontrasting

confidence: 93%

Neuroinflammation facilitates LIF entry into brain: role of TNF

Pan

Yu²,

Hsuchou³

et al. 2008

American Journal of Physiology-Cell Physiology

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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␣, 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.blood-brain barrier; leukemia inhibitory factor; lipopolysaccharide; tumor necrosis factor; nuclear factor-B; neuroinflammation NEUROINFLAMMATION is a syndrome present in many types of disorders affecting the central nervous system (CNS). A commonly used animal model for neuroinflammation involves induction by lipopolysaccharide (LPS), a prototypical endotoxin that promotes the induction of proinflammatory cytokines by acting on CD14 and toll-like receptor 4 (TLR4). Leukemia inhibitory factor (LIF) may be involved in the effects of LPS. This is shown by enhanced induction of tumor necrosis factor-␣ (TNF) and interleukin (IL)-6 in response to LPS in LIF knockout mice (35). After intravenous or intracerebroventricular injection, an anti-LIF antibody can reduce LPS-induced plasma adrenocorticotropin (ACTH) release. This suggests that LIF participates in the actions of LPS both in the periphery and in the CNS to induce neuroendocrine changes (34).LIF and TNF also interact with each other in bacterial infection and sepsis (10). Reciprocal induction and inhibition of the cytokines can occur in a state-dependent manner. Mouse models indicate that exogenous LIF protects against lethal endotoxemia involving a major role for TNF (2, 32). Elevated blood concentrations of LIF, as seen in patients with meningococcemia or septic shock, correlate with higher mortality (31). The role of the CNS response in such actions is not yet clear.LIF is a member of the IL6 family of cytokines that share the gp130 signal converter. LIF binds specifically...

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Section: Discussioncontrasting

confidence: 93%

Neuroinflammation facilitates LIF entry into brain: role of TNF

Pan

Yu²,

Hsuchou³

et al. 2008

American Journal of Physiology-Cell Physiology

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“…At the level of the BBB, TNF not only modulates the functions of the constituent endothelial cells and their tight junctions but also exhibits its own receptor-mediated transport [25][26][27]. We have shown that TNF specifically modulates the expression and functions of the receptors for leukemia inhibitory factor in the cerebral microvessel endothelial cell line RBE4 [28,29]. How TNF regulates the functions of MDR1, a membrane protein encompassing 12-transmembrane domains [2,3], has not been fully characterized.…”

Section: Introductionmentioning

confidence: 99%

TNF Activates P-Glycoprotein in Cerebral Microvascular Endothelial Cells

Kastin

et al. 2007

Cell Physiol Biochem

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Background/Aims: Multidrug resistance proteins (MDRs, including P-glycoproteins) are efflux pumps that serve important biological functions but hinder successful drug delivery to the CNS. Many chemotherapeutic agents, anti-epileptics, anti-HIV drugs, and opiates are substrates for MDRs. Therefore, understanding the regulation of MDRs in the endothelial cells composing the blood-brain barrier has therapeutic implications. Methods: We used microarray, real time RT-PCR, Western blotting, and uptake of vinblastine by RBE4 cerebral endothelial cells to test the effects of tumor necrosis factor alpha (TNF) on the expression and functions of P-glycoprotein (MDR1). Results: The proinflammatory cytokine TNF specifically induced the expression and enhanced the function of MDR1 in RBE4 cells. The persistent upregulation of MDR1 mRNA was shown by cDNA microarray at 6, 12, and 24 h after TNF treatment. This was confirmed by real-time RT-PCR between 2 and 24 h. MDR1 protein expression was increased 6 to 24 h after TNF treatment and resulted in a significant reduction in the cellular uptake of ³H-vinblastine. Conclusion: The drug efflux transporter in cerebral endothelial cells can be upregulated by TNF. This suggests that adjunctive anti-TNF treatment has novel therapeutic potential in conditions such as brain cancer, epilepsy, neuroAIDS, and chronic pain.

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“…The reason for such dissociation of the direction of regulatory changes is not clear, but the involvement of NFκB transcription factor has been proved by use of specific inhibitors. TNF treatment causes a reduction of LIF-induced STAT3 activation and decreases LIF endocytosis by RBE4 cells [34,35]. The results suggest that LIFR (gp190) plays a greater role than gp130 in both LIF transport and signal transduction.…”

Section: Leukemia Inhibitory Factor (Lif) In Sci 4a Lif Transport Inmentioning

confidence: 88%

“…TNF treatment causes a dose-and time-dependent decrease of gp190 protein expression by post-transcriptional regulation, mainly at the level of protein degradation by ubiquitin-proteasome pathways [34]. Concurrently, there is an increase of gp130 mRNA and protein.…”

Section: Leukemia Inhibitory Factor (Lif) In Sci 4a Lif Transport Inmentioning

confidence: 99%

Cytokine Transport Across the Injured Blood-Spinal Cord Barrier

Pan¹,

Kastin²

2008

CPD

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Spinal cord injury (SCI) induces dynamic changes of the blood-spinal cord barrier and even the more distant blood-brain barrier. Besides an immediate increase of paracellular permeability resulting from the direct impact of the injury, the transport systems for selective cytokines undergo regulatory changes. Since many of the transported molecules play essential roles in neuroregeneration, we propose that this altered peripheral tissue / CNS interaction benefits remodeling of the spinal cord and functional recovery after SCI. This review examines the transport of cytokines and neurotrophic factors into the spinal cord, emphasizing the upregulation of two cytokines -tumor necrosis factor α (TNF) and leukemia inhibitory factor (LIF) -during the course of SCI. The increased transport of TNF and LIF after SCI remains saturable and does not coincide with generalized BBB disruption, highlighting a pivotal regulatory role for the bloodspinal cord barrier.

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Opposing effects of proteasomes and lysosomes on LIFR: Modulation by TNF

Cited by 22 publications

References 37 publications

Neuroinflammation facilitates LIF entry into brain: role of TNF

Neuroinflammation facilitates LIF entry into brain: role of TNF

TNF Activates P-Glycoprotein in Cerebral Microvascular Endothelial Cells

Cytokine Transport Across the Injured Blood-Spinal Cord Barrier

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