Both soluble and membrane-associated TNF activate brain microvascular endothelium: relevance to multiple sclerosis

Burger, Danielle; Lou, Jinning; Jm, Dayer; Grau, Georges E.

doi:10.1038/sj.mp.4000221

Cited by 13 publications

(8 citation statements)

References 4 publications

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“…Knock-in of an uncleavable, membrane-bound, pro-TNF-␣ allele onto the TNF null background, which completely eliminates inducible cleavage of pro-TNF-␣ and therefore, generation of soluble TNF-␣, rescues only a subset of defects seen in TNF null mice [95]. Mice expressing uncleavable pro-TNF-␣ are still resistant to endotoxic shock and show defects in leukocyte trafficking [95], but the mice rescue TNF-␣-null defects in secondary lymphoid organ structure [95] and display cytotoxic activity, activation of B and T cells [96,97], and endothelial cells [98].…”

Section: Ectodomain Shedding Can Rapidly Regulate Leukocyte-endothelimentioning

confidence: 94%

Emerging roles for ectodomain shedding in the regulation of inflammatory responses

Garton

Gough

Raines

2006

Journal of Leukocyte Biology

207

194

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The multistep model of leukocyte recruitment to sites of inflammation has helped elucidate specific molecular cues for each of the individual steps. However, it is less clear how cells transition between the different steps and how the complex interactions are coordinately regulated. Once a leukocyte sticks to the endothelium, it only takes a few minutes to reach the subendothelial basement membrane, so the transitions and regulatory mechanisms must be rapid. We put forward the hypothesis that proteolytic shedding of cell surface proteins provides a mechanism to aid in the rapid transition of cells and coordinate the complex, multistep process of leukocyte recruitment in response to inflammatory stimuli. Support for this hypothesis is provided from analyses of disease states and from studies with protease inhibitors and genetically engineered mutations that prevent "ectodomain shedding" of cell surface proteins and consequently perturb the inflammatory response.

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Section: Ectodomain Shedding Can Rapidly Regulate Leukocyte-endothelimentioning

confidence: 94%

Emerging roles for ectodomain shedding in the regulation of inflammatory responses

Garton

Gough

Raines

2006

Journal of Leukocyte Biology

207

194

View full text Add to dashboard Cite

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“…Furthermore, mTNF-· is also involved in other biological processes, such as the activation of polyclonal B cells induced by human immune deficiency virus-1 (HIV-1) or human T cell leukemia virus (HTLV) I-infected CD4 + T cells (6,7), production of IL-10 from monocytes (8), and expression of ICAM-1 by endothelial cells (9). All of these biological effects of mTNF-· are likely mediated through both TNF receptor types, in which mTNF-· is the primary activating ligand of TNF receptor II (TNFRII) (10).…”

Section: Introductionmentioning

confidence: 99%

Dual regulation of soluble tumor necrosis factor-α induced activation of human monocytic cells via modulating transmembrane TNF-α-mediated ‘reverse signaling’

Luo¹,

Wang²,

Zhang³

et al. 2006

Int J Mol Med

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Abstract.Transmembrane tumor necrosis factor-· (mTNF-·) is known to be the precursor of soluble TNF-· (sTNF-·). mTNF-· can act as a ligand on the TNF receptor-(TNFR)-bearing cell through 'forward signaling' or as a receptor on the TNF producing cell through 'reverse signaling'. In the current study, we investigated the role of mTNF-·-mediated reverse signaling in regulating sTNF-·-induced activation of human monocytic U937 cells. We demonstrated that pretreatment with sTNFRI, for inducing reverse signaling through mTNF-·, sensitized U937 cells to sTNF-· stimulation, as evidenced by an increase in reactive oxygen production and mRNA levels of proinflammatory cytokines (TNF-·, IL-1ß, and IL-8) in these cells. Further experiments revealed that IκB-· degradation was increased in the monocytic cells primed with sTNFRI, implying that reverse signaling of mTNF-· sensitizes U937 cells via an NF-κB-dependent mechanism. On the other hand, binding of sTNFRI to mTNF-· after sTNF-·-induced activation of U937 cells reduced mRNA stability (half-life) of IL-1ß and IL-8. The involvement of reverse signaling in the process was verified by using a mutated form of mTNF-· lacking the majority of the cytoplasmic domain. Our results clearly showed that enhanced mRNA degradation of the cytokines occurred only in U937 cells transfected with a wild-type mTNF-·, but not in those cells transfected with the mutant mTNF-·. Taken together, these data suggest that reverse signaling through mTNF-· may exert a double role in modulating sTNF-· bioactivity. It is positive when reverse signaling occurs prior to sTNF-· stimulation, while it is negative when reverse signaling occurs after the sTNF-· signal. Thus, our findings strengthen a role of mTNF-·-mediated reverse signaling in the regulation of immune-inflammatory response and control of inflammatory reaction.

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“…It has been demonstrated that platelets act in vitro as effectors of vascular endothelium damage, after TNF stimulation of brain EC (11). So far, the effect of both platelets and PRBC on functional changes or viability of human brain EC (HBEC) has not been studied in a coculture model of CM.…”

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confidence: 99%

Platelets Potentiate Brain Endothelial Alterations Induced byPlasmodium falciparum

et al. 2006

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Brain lesions of cerebral malaria (CM) are characterized by a sequestration of Plasmodium falciparumparasitized red blood cells (PRBC) and platelets within brain microvessels, as well as by blood-brain barrier (BBB) disruption. In the present study, we evaluated the possibility that PRBC and platelets induce functional alterations in brain endothelium. In a human brain endothelial cell line, named HBEC-5i, exhibiting most of the features demanded for a pathophysiological study of BBB, tumor necrosis factor (TNF) or lymphotoxin ␣ (LT-␣) reduced transendothelial electrical resistance (TEER), enhanced the permeability to 70-kDa dextran, and increased the release of microparticles, a recently described indicator of disease severity in CM patients. In vitro cocultures showed that platelets or PRBC can have a direct cytotoxic effect on activated, but not on resting, HBEC-5i cells. Platelet binding was required, as platelet supernatant had no effect. Furthermore, platelets potentiated the cytotoxicity of PRBC for TNF-or LT-␣-activated HBEC-5i cells when they were added prior to these cells on the endothelial monolayers. This effect was not observed when platelets were added after PRBC. Both permeability and TEER were strongly affected, and the apoptosis rate of HBEC-5i cells was dramatically increased. These findings provide insights into the mechanisms by which platelets can be deleterious to the brain endothelium during CM.

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Both soluble and membrane-associated TNF activate brain microvascular endothelium: relevance to multiple sclerosis

Cited by 13 publications

References 4 publications

Emerging roles for ectodomain shedding in the regulation of inflammatory responses

Emerging roles for ectodomain shedding in the regulation of inflammatory responses

Dual regulation of soluble tumor necrosis factor-α induced activation of human monocytic cells via modulating transmembrane TNF-α-mediated ‘reverse signaling’

Platelets Potentiate Brain Endothelial Alterations Induced byPlasmodium falciparum

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