Neuroinflammation facilitates LIF entry into brain: role of TNF

Abstract

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...

Interleukin-6 in Surgery, Trauma, and Critical Care Part II: Clinical Implications

“…Meanwhile, elevated LIF concentrations are also noted in septic patients and are associated with adverse outcome. 64 Similarly, OSM concentrations are increased in patients with septic shock. 65 …”

“…64 Lipopolysaccharide stimulation can increase gp130 mRNA expression in endothelial cells, suggesting that the blood-brain barrier would then become responsive to the IL-6 family of cytokines. 64 It has been further proposed that cytokine translocation across an altered blood-brain barrier following traumatic brain injury may play an important role in the subsequent development of multiorgan failure. 29 The next several articles demonstrate these findings.…”

Analytic Review: Interleukin-6 in Surgery, Trauma, and Critical Care: Part I: Basic Science

“…21 Elevated LIF concentrations have been noted with sepsis and correlated with adverse outcome. 33,34 …”

Interactions Between Reproductive and Immune Systems During Ontogeny: Roles of GnRH, Sex Steroids, and Immunomediators

“…Under the effect of LPS, these cells, along with cells of the immune system, can synthesize proinflammatory cytokines such as IL-1 , IL-1 , and IL-6; tumor necrosis factor alpha (TNF ); regulatory cytokine IL-10; and granulocyte/macrophage colony-stimulating factor (GM-CSF). Bacterial inflammation is also accompanied by an increase of another proinflammatory cytokine, the leukemia inhibitory factor (LIF) in the blood level, which penetrates the hematoencephalic barrier via a special transport system (Pan et al, 2008). Thus, bacterial inflammation stimulates signal transmission through vascular endothelium and cytokine transport through the hematoencephalic barrier.…”