PubMed · 14655691
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U K Naumann, L Käser, W Vetter. 2003-09-17. [Hypercalcemia].. https://doi.org/10.1024/0369-8394.92.38.1567
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Glucocorticoid hormones induce apoptosis in lymphoid cells. This process is transcriptionally regulated and requires de novo RNA/protein synthesis. However, the full spectrum of glucocorticoid-regulated genes mediating this cell death process is unknown. Through gene expression profiling we discovered that the expression of thioredoxin-intereacting protein (txnip) mRNA is significantly induced by the glucocorticoid hormone dexamethasone not only in the murine T-cell lymphoma line WEHI7.2, but also in normal mouse thymocytes. This result was confirmed by Northern blot analysis in multiple models of dexamethasone-induced apoptosis. The induction of txnip mRNA by dexamethasone appears to be mediated through the glucocorticoid receptor as it is blocked in the presence of RU486, a glucocorticoid receptor antagonist. Deletion and mutation analysis of the txnip promoter identified a functional glucocorticoid response element in the txnip promoter. Reporter assays demonstrated that this glucocorticoid response element was necessary and sufficient for induction of txnip by dexamethasone. Expression of a GFP-TXNIP fusion protein was sufficient to induce apoptosis in WEHI7.2 cells, and repression of endogenous txnip by RNA interference inhibited dexamethasone-induced apoptosis in WEHI7.2 cells. Together, these findings indicate that txnip is a novel glucocorticoid-induced primary target gene involved in mediating glucocorticoid-induced apoptosis.
HISTORY AND ADMISSION FINDINGS: A 46-year-old, having developed developed gross haematuria and pain in the genital region, was referred to a urological unit. Because palpation of his prostatic gland was abnormal, a transurethral prostatic resection was performed. The histology showed a necrotizing and granulomatous inflammation of the prostate with small-vessel vasculitis and eosinophilic infiltrates. As the patient had also developed arthralgia and symptoms in the upper respiratory tract, he was admitted to our hospital. The test for c-ANCA with specifity for proteinase 3 was positive. There was no history or symptoms of asthma. DIAGNOSIS: Wegener's granulomatosis. TREATMENT AND COURSE: To achieve remission bolus therapy with cyclophosphamide and prednisolone was initiated and planned to be the first of three pulses But when the patient developed epididymitis and a neuropathy associated with Wegener"s granulomatosis, the dose was increased and cyclophosphamide was given for a longer period. CONCLUSION: The early manifestation of Wegener"s granulomatosis at the prostatic gland is rare in this disease. This case presented with an impressive variation of symptoms, which may occur especially in the early course of vasculitis. The findings of c-ANCA with specifity for proteinase 3 is important for the diagnosis of this disease.
Protein C is a plasma protease that when activated plays a central role in modulating the function of the vascular endothelium and its interface with the innate immune system. A recombinant form of human activated protein C (APC), drotrecogin alfa (activated), has shown efficacy in a number of preclinical models of thrombosis and ischemia and reduces mortality in patients that have a high risk of dying from severe sepsis. Studies have begun to elucidate the mechanism for the multifunctional role of APC in modulating not only coagulation, but also inflammation and apoptotic processes. From gene profiling to pharmacology studies, drotrecogin alfa (activated) appears to directly modulate endothelial dysfunction by blocking cytokine signaling, functional cell adhesion expression, vascular permeability and preventing the induction of apoptosis. Moreover, APC, via endothelial protein C receptor/protease activated receptor-1 mediated mechanisms, also appears to directly modulate leukocyte migration and adhesion. The ability of APC to suppress pro-inflammatory pathways and enhance cellular survival suggests that APC has a role in the adaptive response at the vessel wall, in which it protects the wall from vascular insult and prolongs endothelial, cellular, and organ survival. The emerging data further suggest that APC effectively modulates the complex changes that occur during multi-system activation and dysfunction in sepsis.