Induction of the cytokine TWEAK and its receptor Fn14 in ischemic stroke
Introduction
Despite the advances that have been made in recanalization therapy, ischemic stroke is still difficult to treat in the majority of patients because thrombolysis is only possible for a few hours after onset of symptoms. Delayed mechanisms of ischemic brain injury, such as neuronal apoptosis in the penumbra or brain edema, hold promise of falling into a wider time window amenable to therapy. Recent evidence suggests that the cytokine tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is involved in the delayed phase of ischemic brain injury.
TWEAK belongs to the TNF family [1]. It binds to the membrane receptor Fn14, a member of the TNF receptor superfamily. TWEAK was first identified as a proapototic cytokine in tumor cells but it also promotes inflammation and angiogenesis [1]. In a mouse model of stroke, TWEAK expression was enhanced two-fold in the ischemic brain [2]. Furthermore, the TWEAK receptor Fn14 was upregulated 22-fold. Interestingly, TWEAK contributes to ischemic brain damage because a neutralizing anti-TWEAK antibody reduces the infarct size. Subsequently, other means of interfering with TWEAK–Fn14 signaling were also shown to be protective. In a similar mouse model of stroke, a soluble Fn14-Fc decoy receptor and genetic deficiency of Fn14 reduced the infarct size [3], [4], confirming the important role of TWEAK and Fn14 in cerebral ischemia. TWEAK–Fn14 seems to promote ischemic brain damage through two mechanisms. First, recombinant TWEAK has been shown to trigger apoptosis in neurons in vitro by activating the transcription factor NF-κB [2]. TWEAK stimulates NF-κB activity in the ischemic brain [4] and NF-κB signaling contributes to ischemia-induced neuronal cell death in vivo as well [5]. NF-κB may also be involved in the second mechanism of TWEAK-induced brain damage: TWEAK increases the permeability of the blood-brain barrier and thereby enhances brain edema in stroke [4]. Thus, a TWEAK antagonist may be neuroprotective and limit brain edema. The case of TNF illustrates that drugs can be successfully developed to target cytokines of this family. However, the role of TWEAK in stroke patients has been unclear. Therefore, we investigated TWEAK plasma levels in stroke patients and TWEAK and Fn14 expression in the brain tissue of human stroke patients.
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Subjects
In this study we included 27 patients treated for acute ischemic stroke in our clinic. All patients were admitted to our hospital within the first 24 h after onset of symptoms. On admission a CT or MR scan was performed in all patients. The control group was recruited in parallel. Control patients were sex- and age-matched and had been admitted to the Department of Ophthalmology for elective cataract surgery or glaucoma therapy. The stroke patients were treated with anticoagulants (heparin or
Increased serum levels of TWEAK in stroke patients
The clinical and demographic data for our study population are summarized in Table 1. The time interval between onset of stroke symptoms and blood sampling was 7.4 h on average. TWEAK serum concentrations were measured with a commercial ELISA kit. An in-house ELISA confirmed the results (data not shown). In control subjects TWEAK levels were comparable to levels determined with another assay [7]. Interestingly, in the stroke patients TWEAK serum concentrations were significantly higher than in
Discussion
Our data suggest that TWEAK and its membrane receptor Fn14 may be involved in stroke. TWEAK was identified as a secreted member of the TNF superfamily of cytokines [9]. We found elevated serum concentrations of TWEAK in stroke patients within 24 h after stroke onset, which may represent a spillover from the brain if the trend towards elevated mRNA levels in infarct tissue is correctly indicating an induction of TWEAK expression in stroke. Previous work on TWEAK expression in a mouse model of
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