The combination of TRAIL and MG-132 induces apoptosis in both TRAIL-sensitive and TRAIL-resistant human follicular lymphoma cells.

We have previously shown that the human follicular lymphoma cell line, HF28GFP, is sensitive to TRAIL-mediated apoptosis. Nevertheless, when the same cells overexpress anti-apoptotic Bcl-2 family protein, Bcl-xL (HF28Bcl-xL), they become resistant to TRAIL. Thus, these cell lines help us to investigate the action of novel apoptosis inducing candidate drugs.

Advantages of targeting B cell receptor complex to treat B-cell derived autoimmune diseases and lymphomas.

Antibodies produced by B-cells provide protection from infectious agents. However, impaired cell death signaling pathways in B-cells can lead to cancer, immunodeficiency or autoimmune diseases. B-cell signaling molecules such as CD20, CD19, Btk, and BAFF-R are targeted by therapeutic drugs and used to treat B-cell derived lymphomas or autoimmune diseases.

RIP1 has a role in CD40-mediated apoptosis in human follicular lymphoma cells.

CD40 is a cell surface receptor which belongs to tumor necrosis factor receptor (TNFR) family members. It transmits signals that regulate diverse cellular responses such as proliferation, differentiation, adhesion molecule expression and apoptosis. Unlike other TNFR family members (TRAIL-R, Fas-R and TNFR1), the CD40 cytoplasmic tail lacks death domain.

Timing determines dexamethasone and rituximab induced synergistic cell death.

Dysregulation of cell death signaling pathways in many cell types such as B lymphocytes (B-cells) can lead to cancer, for example to B-cell lymphomas. Rituximab (RTX) and glucocorticoids such as dexamethasone (Dex) are widely used to treat hematological malignancies including B-cell lymphomas. Although the combination of Dex and RTX improves the treatment outcome of lymphoma patients, most lymphomas remain incurable diseases.

Differential Expression of Bcl-2 Family Proteins Determines the Sensitivity of Human Follicular Lymphoma Cells to Dexamethasone-mediated and Anti-BCR-mediated Apoptosis.

Bcl-2 family comprises proapoptotic and antiapoptotic proteins. The balance between these proteins is critical for the survival of the cells. Overexpression of the antiapoptotic protein, Bcl-2, is the hallmark of follicular lymphoma (FL).

ERK1/2 has an essential role in B cell receptor- and CD40-induced signaling in an in vitro model of germinal center B cell selection.

Germinal center (GC) B cells undergo apoptosis after B cell receptor (BCR) ligation, unless they receive CD40-mediated survival signal from helper T cells. In the present study, we used a human follicular lymphoma cell line HF1A3, as an in vitro model to study the selection process in germinal centers. We show here that BCR ligation led to immediate ERK1/2 activation and phosphorylations of its downstream targets, Bim EL/L and Bcl-2 (at Ser70) which resulted in short-term survival.

Rituximab-induced early and late signaling have opposite effects on dexamethasone-induced apoptosis in human follicular lymphoma cells.

The addition of rituximab (RTX) to standard chemotherapy has improved the treatment of B-cell malignancies. We show here that RTX and dexamethasone (Dex) induced synergistic apoptosis in follicular lymphoma cell lines. However, apoptosis was delayed by RTX-induced early protective signaling.

Dexamethasone-induced apoptosis and up-regulation of Bim is dependent on glycogen synthase kinase-3.

Glucocorticoids are commonly used in the treatment of lymphoid malignancies. In this study, we show that apoptosis induced by dexamethasone (Dex), a synthetic glucocorticoid, was dependent on mitochondria, since overexpression of Bcl-X(L) prevented Dex-induced apoptotic changes. Dominant negative (DN) caspase-9 also prevented Dex-induced apoptotic changes including the loss of mitochondrial membrane potential indicating that caspase-9 controls mitochondrial changes.

The involvement of mitochondria and the caspase-9 activation pathway in rituximab-induced apoptosis in FL cells.

Despite the wide use of anti-CD20 antibody rituximab in the cancer treatment of B cell malignancies, the signalling pathways of CD20-induced apoptosis are still not understood. By using dominant negative (DN)-caspase-9 overexpressing follicular lymphoma cells we demonstrated that the activation of caspase-9 was essential for rituximab-mediated apoptosis. The death receptor pathway mediated by caspase-8 activation was not involved in rituximab-mediated apoptosis since overexpression of FLIP(short) or FLIP(long) proteins, inhibitors of caspase-8 activation, could not inhibit rituximab-induced apoptosis.

PDTC enables type I TRAIL signaling in type II follicular lymphoma cells.

Based on Bcl-X(L) overexpression studies we identified type I and type II follicular lymphoma cell lines in response to TRAIL. We demonstrate here that either amount of caspase-8 activation or Bid cleavage could not define the dependence on mitochondria. Furthermore, an inhibitor of NF-kappaB, PDTC, enabled TRAIL to activate type I apoptotic pathway in type II cells.

The CD40-induced protection against CD95-mediated apoptosis is associated with a rapid upregulation of anti-apoptotic c-FLIP.

CD95/Fas and CD40 receptors are important regulators of cell survival during germinal center reaction. In this study we used a human follicular lymphoma cell line, HF1A3, to study molecular mechanisms of CD95-mediated apoptosis and CD40-induced rescue from apoptosis. CD95 stimulation induced activation of caspase-8 and -3, collapse of mitochondrial membrane potential (DeltaPsim), release of cytochrome c and fragmentation of nuclear DNA.

Inhibition of PI3-kinase-Akt pathway enhances dexamethasone-induced apoptosis in a human follicular lymphoma cell line.

Glucocorticoids are commonly used in the treatment of various lymphoid malignancies. In the present study, we show that dexamethasone (Dex) induced depolarization of mitochondrial membrane, release of cytochrome c and DNA fragmentation in a human follicular lymphoma cell line, HF28RA. New protein synthesis was required before Dex-induced mitochondrial changes, and the kinetics of the apoptotic events correlated with the upregulation of the Bim protein.

Synergistic interaction in simultaneous exposure to Streptomyces californicus and Stachybotrys chartarum.

The microbial exposure associated with health complaints in moldy houses consists of a heterogeneous group of components, including both living and dead bacteria, fungi, and their metabolites and active compounds. However, little is known about the interactions between different microbes and their metabolites, although the cytotoxicity and inflammatory potential of certain individual microbes have been reported. In this study, we investigated the inflammatory responses of mouse RAW264.

Kinetics and signaling requirements of CD40-mediated protection from B cell receptor-induced apoptosis.

In the present study we used a human follicular lymphoma cell line, HF1A3, as an in vitro model for the antigen-driven selection process in germinal centers. Apoptosis can be induced in HF1A3 cells by B cell receptor (BCR) stimulation, but the molecular mechanisms and kinetics of this process are largely unknown. We demonstrate here that there is over 12 h delay between receptor activation and the execution phase of apoptosis, i.