Elke Boone

The nuclear factor-kappa B engages CBP/p300 and histone acetyltransferase activity for transcriptional activation of the interleukin-6 gene promoter.

Expression of the pleiotropic cytokine interleukin (IL)-6 can be stimulated by the proinflammatory cytokine tumor necrosis factor (TNF) and the microbial alkaloid staurosporine (STS). In this report, the transcriptional mechanisms were thoroughly investigated. Whereas transcription factors binding to the activator protein-1-, cAMP-responsive element-, and CAAT enhancer-binding protein-responsive sequences are necessary for gene activation by STS, nuclear factor (NF)-κB alone is responsible and sufficient for inducibility by TNF, which reveals distinct signaling pathways for both compounds. At the cofactor level, cAMP-responsive element-binding protein-binding protein (CBP) or p300 potentiate basal and induced IL-6 promoter activation via multiple protein-protein interactions with all transcription factors bound to the promoter DNA. However, the strongest promoter activation relies on the p65 NF-κB subunit, which specifically engages CBP/p300 for maximal transcriptional stimulation by its histone acetyltransferase activity. Moreover, treatment of chromatin-integrated promoter constructions with the histone deacetylase inhibitor trichostatin A exclusively potentiates TNF-dependent (i.e. NF-κB-mediated) gene activation, while basal or STS-stimulated IL-6 promoter activity remains completely unchanged. Similar observations were recorded with other natural NF-κB-driven promoters, namely IL-8 and endothelial leukocyte adhesion molecule (ELAM). We conclude that, within an “enhanceosome-like” structure, NF-κB is the central mediator of TNF-induced IL-6 gene expression, involving CBP/p300 and requiring histone acetyltransferase activity.

Attenuation of Mitogen- and Stress-Activated Protein Kinase-1–Driven Nuclear Factor-κB Gene Expression by Soy Isoflavones Does Not Require Estrogenic Activity

We have analyzed in molecular detail how soy isoflavones (genistein, daidzein, and biochanin A) suppress nuclear factor-kappaB (NF-kappaB)-driven interleukin-6 (IL6) expression. In addition to its physiologic immune function as an acute stress cytokine, sustained elevated expression levels of IL6 promote chronic inflammatory disorders, aging frailty, and tumorigenesis. Our results in estrogen-unresponsive fibroblasts, mitogen- and stress-activated protein kinase (MSK) knockout cells, and estrogen receptor (ER)-deficient breast tumor cells show that phytoestrogenic isoflavones can selectively block nuclear NF-kappaB transactivation of specific target genes (in particular IL6), independently of their estrogenic activity. This occurs via attenuation of mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK) and ERK activity, which further down-regulates MSK-dependent NF-kappaB p65 and histone H3 phosphorylation. As constitutive NF-kappaB and MSK activity are hallmarks of aggressive metastatic ER-deficient breast cancer, the MSK signaling pathway may become an attractive target for chemotherapy.

Activation of p42/p44 mitogen-activated protein kinases (MAPK) and p38 MAPK by tumor necrosis factor (TNF) is mediated through the death domain of the 55-kDa TNF receptor

In the mouse fibrosarcoma cell line L929sA, tumor necrosis factor (TNF) stimulates activation of the stress‐responsive p38 mitogen‐activated protein kinase (MAPK), as well as the classical p42 and p44 MAPK. TNF signaling can be mediated by p55 or p75 TNF receptors. Here, we demonstrate that TNF‐R55 is sufficient to activate p42/p44 MAPK and p38 MAPK. Moreover, by expressing different membrane‐bound or purely cytoplasmic truncations of TNF‐R55, we show that the intracellular death domain of TNF‐R55 is the crucial domain involved. The cytoplasmic membrane‐proximal region of TNF‐R55, known to induce neutral sphingomyelinase activation, is not required for activation of p38 MAPK or p42/p44 MAPK.

A case of Candida lambica fungemia misidentified as Candida krusei in an intravenous drug abuser

Only a handful of cases of human Candida lambica infections have been published up to now. We report a Candida lambica fungemia in a young intravenous drug abuser. Using a popular chromogenic agar and a commercial phenotyping gallery, the fungus was initially misidentified as Candida krusei. Key tests to distinguish these closely related species are maximum growth temperature and assimilation of certain substrates present in more elaborate phenotyping assays. Definite confirmation is possible using molecular techniques. Susceptibility testing of the isolate demonstrated amphotericin B (MIC 0.125 microg/ml) susceptible, flucytosine (MIC 2 microg/ml) susceptible, itraconazole (MIC 0.064 microg/ml) susceptible, voriconazole (MIC 1 microg/ml) susceptible, and fluconazole (MIC >64 microg/ml, resistant).

Clonal multicentric Castleman’s disease with increased free kappa light chains in a patient with systemic lupus erythematosus

Dear Editor, Castleman’s disease (CD) is a heterogeneous, Blymphoproliferative disorder linked in some patients to human immunodeficiency virus (HIV) and/or human herpes virus 8 (HHV-8) infection. Clinically, CD is classified as unicentric (localized) or multicentric. Fatal cases of MCD are associated with fulminant infection, progressive disease including progression to lymphoma and related malignancies. The majority of unicentric CD is hyaline vascular type and presents with localized mass effect or asymptomatic. Multicentric CD is mostly plasma cell (PC) type and presents with disseminated lymphadenopathy, systemic symptoms (fever, fatigue, sweating, and weight loss), hepatosplenomegaly, and can be associated with autoimmune disease [1–4]. These PCs are usually polyclonal, but may be monotypic and usually lambda light chain restricted (IgG or IgA), especially in the PC–CD associated with osteosclerotic myeloma, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome [5]. Monoclonality is rare and may herald development of lymphoma [6, 7]. A 44-year-old, HIV-negative female patient, presented with fatigue, night sweats, weight loss of 7 kg in 4 months, and abdominal lymphadenopathies. She had been diagnosed with systemic lupus erythematosus (SLE) 30 years earlier for which she was treated with splenectomy and multiple immunosuppressants. Hematological investigations revealed a WBC count of 5.29×10 cells/μL (reference range, 3.90– 11.10×10/μL) with 50 % neutrophils (reference range, 46– 64 %), a hemoglobin level of 12.2 g/dL (reference range, 11.8–14.8 g/dL), and a platelet count of 452×10/μL (reference range, 150–450×10/μL). Biochemical findings included a slightly increased C-reactive protein (CRP; 1.9 mg/dL (reference range, 0.00–0.70 mg/dL)), normal LDH (392 U/L (reference range, 240–480 U/L)), elevated erythrocyte sedimentation rate (49 mm (reference range, 1–14 mm)), and normal renal function. Serum electrophoresis revealed hypergammaglobulinemia with elevated IgG (2,300 mg/dL (reference range, 700–1,600 mg/dL)) and hypoalbuminemia. Using immunofixation, no M-protein was detectable. Free light kappa and lambda chains (The Binding Site Ltd, Birmingham, UK) were increased with dominance for kappa (kappa, 112 mg/L (reference range, 3.30–19.4 mg/L), 30.0 lambda (reference range, 5.70–26.3 mg/L), and 3.73 ratio (reference range, 0.26–1.65)). β2-microglobuline was elevated to 0.539 mg/dL (reference range, 0.109–0.253 mg/dL). Antinuclear autoantibodies, extractable nuclear antibodies, and positivity on a direct coombs test were found. Diagnostic criteria for POEMS syndrome, monoclonal gammopathy (e.g., monoclonal gammopathy of undetermined significance and multiple myeloma), and SLE were not fulfilled [8, 9]. PET-CT showed multiple unequally sized nodules in the mediastinal, abdominal, and inguinal regions (Fig. 1a). An oval-shaped, right inguinal lymph gland of 2.2 cm was M. Oyaert : E. Moreau :H. Vanpoucke Clinical Laboratory, AZ Delta Roeselare Menen, Roeselare, Belgium