Tumor necrosis factor is elevated in progressive multiple sclerosis and causes excitotoxic neurodegeneration

2013 ◽  
Vol 20 (3) ◽  
pp. 304-312 ◽  
Author(s):  
Silvia Rossi ◽  
Caterina Motta ◽  
Valeria Studer ◽  
Francesca Barbieri ◽  
Fabio Buttari ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Neuronal Damage ◽  
Brain Slices ◽  
Progressive Multiple Sclerosis ◽  
Cell Swelling ◽  
Necrosis Factor

Background: Chronic inflammation leads to gray matter damage in progressive multiple sclerosis (MS), but the mechanism linking inflammation and neurodegeneration is unclear. Objective: The objective of this paper is to investigate the synaptic mechanism of inflammatory neurodegeneration in progressive forms of MS. Methods: Cytokine and neurofilament-light were determined in cerebrospinal fluid (CSF) of MS patients. In vitro electrophysiology and cell swelling experiments were performed to measure the effects of inflammatory cytokines in the CSF of MS patients on synaptic transmission and neuronal integrity. Results: Tumor necrosis factor-α (TNF) was higher in CSF of progressive MS subjects, and caused excitotoxic neuronal death in vitro. In murine brain slices incubated in the presence of CSF from progressive MS, in fact, we observed increased spontaneous excitatory postsynaptic currents (sEPSCs) and glutamate-mediated neuronal swelling through a mechanism dependent on enhanced TNF signaling. We also suggested a pathogenic role of B cells in TNF CSF increase, exacerbation of glutamatergic transmission and neuronal damage, since CNS depletion of B cells with intrathecal rituximab caused a dramatic reduction of TNF levels, of TNF-induced sEPSC alterations, and of neurofilament CSF concentrations in a patient with progressive MS. Conclusion: Our results point to TNF as a primary neurotoxic molecule in progressive forms of MS.

scholarly journals TRANCE (Tumor Necrosis Factor [TNF]-related Activation-induced Cytokine), a New TNF Family Member Predominantly Expressed in T cells, Is a Dendritic Cell–specific Survival Factor

1997 ◽  
Vol 186 (12) ◽  
pp. 2075-2080 ◽  
Author(s):  
Brian R. Wong ◽  
Régis Josien ◽  
Soo Young Lee ◽  
Birthe Sauter ◽  
Hong-Li Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Dominant Negative ◽  
Mouse Bone Marrow ◽  
Survival Factor ◽  
Necrosis Factor

TRANCE (tumor necrosis factor [TNF]–related activation-induced cytokine) is a new member of the TNF family that is induced upon T cell receptor engagement and activates c-Jun N-terminal kinase (JNK) after interaction with its putative receptor (TRANCE-R). In addition, TRANCE expression is restricted to lymphoid organs and T cells. Here, we show that high levels of TRANCE-R are detected on mature dendritic cells (DCs) but not on freshly isolated B cells, T cells, or macrophages. Signaling by TRANCE-R appears to be dependent on TNF receptor–associated factor 2 (TRAF2), since JNK induction is impaired in cells from transgenic mice overexpressing a dominant negative TRAF2 protein. TRANCE inhibits apoptosis of mouse bone marrow–derived DCs and human monocyte-derived DCs in vitro. The resulting increase in DC survival is accompanied by a proportional increase in DC-mediated T cell proliferation in a mixed leukocyte reaction. TRANCE upregulates Bcl-xL expression, suggesting a potential mechanism for enhanced DC survival. TRANCE does not induce the proliferation of or increase the survival of T or B cells. Therefore, TRANCE is a new DC-restricted survival factor that mediates T cell–DC communication and may provide a tool to selectively enhance DC activity.

scholarly journals Tumor necrosis factor induces proliferation of neoplastic B cells from chronic lymphocytic leukemia

Blood ◽  
1989 ◽  
Vol 73 (5) ◽  
pp. 1242-1246 ◽  
Author(s):  
W Digel ◽  
M Stefanic ◽  
W Schoniger ◽  
C Buck ◽  
A Raghavachar ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Lymphocytic Leukemia ◽  
Membrane Receptors ◽  
Necrosis Factor Alpha ◽  
Proliferative Effect ◽  
Necrosis Factor

Abstract The biologic effects of recombinant tumor necrosis factor-alpha (rTNF- alpha) and the expression of specific TNF membrane receptors on isolated neoplastic B cells from previously untreated patients with chronic lymphocytic leukemia (CLL) were investigated in vitro. Isolated B cells were incubated up to six days with various concentrations of rTNF-alpha (0.1 to 100 ng/mL). B cells from most patients proliferated ranged from two to 104 times that of unstimulated cells from the same patients. An optimal proliferative effect was achieved at 25 ng/mL rTNF- alpha and an incubation time between 96 and 120 hours, whereas a low concentration of rTNF-alpha (1 ng/mL) reduced [3H]TdR incorporation in four cases. Metaphase cells were detected in the rTNF-alpha-stimulated cultures that proliferated in response to rTNF-alpha. B cells from three of ten patients proliferated spontaneously and proliferation was further enhanced in two patients by rTNF-alpha. TNF binding assays gave a value of approximately 390 to 1,400 binding sites/cell for TNF and a dissociation constant (kd) of approximately 60 pmol/L. These data indicate that rTNF-alpha, in contrast to its cytotoxic/cytostatic effects, can also induce proliferation of tumor cells.

scholarly journals Generation of Splenic Follicular Structure and B Cell Movement in Tumor Necrosis Factor–deficient Mice

1998 ◽  
Vol 188 (8) ◽  
pp. 1503-1510 ◽  
Author(s):  
Matthew C. Cook ◽  
Heinrich Körner ◽  
D. Sean Riminton ◽  
Frances A. Lemckert ◽  
Jhagvaral Hasbold ◽  
...  
Keyword(s):  
B Cells ◽  
Tumor Necrosis Factor ◽  
B Cell ◽  
Tumor Necrosis ◽  
Cell Movement ◽  
Wild Type ◽  
Germinal Center Reaction ◽  
Necrosis Factor

Secondary lymphoid tissue organogenesis requires tumor necrosis factor (TNF) and lymphotoxin α (LTα). The role of TNF in B cell positioning and formation of follicular structure was studied by comparing the location of newly produced naive recirculating and antigen-stimulated B cells in TNF−/− and TNF/LTα−/− mice. By creating radiation bone marrow chimeras from wild-type and TNF−/− mice, formation of normal splenic B cell follicles was shown to depend on TNF production by radiation-sensitive cells of hemopoietic origin. Reciprocal adoptive transfers of mature B cells between wild-type and knockout mice indicated that normal follicular tropism of recirculating naive B cells occurs independently of TNF derived from the recipient spleen. Moreover, soluble TNF receptor–IgG fusion protein administered in vivo failed to prevent B cell localization to the follicle or the germinal center reaction. Normal T zone tropism was observed when antigen-stimulated B cells were transferred into TNF−/− recipients, but not into TNF/LTα−/− recipients. This result appeared to account for the defect in isotype switching observed in intact TNF/LTα−/− mice because TNF/LTα−/− B cells, when stimulated in vitro, switched isotypes normally. Thus, TNF is necessary for creating the permissive environment for B cell movement and function, but is not itself responsible for these processes.

scholarly journals Tumor necrosis factor induces proliferation of neoplastic B cells from chronic lymphocytic leukemia

Blood ◽  
1989 ◽  
Vol 73 (5) ◽  
pp. 1242-1246
Author(s):  
W Digel ◽  
M Stefanic ◽  
W Schoniger ◽  
C Buck ◽  
A Raghavachar ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Lymphocytic Leukemia ◽  
Membrane Receptors ◽  
Necrosis Factor Alpha ◽  
Proliferative Effect ◽  
Necrosis Factor

The biologic effects of recombinant tumor necrosis factor-alpha (rTNF- alpha) and the expression of specific TNF membrane receptors on isolated neoplastic B cells from previously untreated patients with chronic lymphocytic leukemia (CLL) were investigated in vitro. Isolated B cells were incubated up to six days with various concentrations of rTNF-alpha (0.1 to 100 ng/mL). B cells from most patients proliferated ranged from two to 104 times that of unstimulated cells from the same patients. An optimal proliferative effect was achieved at 25 ng/mL rTNF- alpha and an incubation time between 96 and 120 hours, whereas a low concentration of rTNF-alpha (1 ng/mL) reduced [3H]TdR incorporation in four cases. Metaphase cells were detected in the rTNF-alpha-stimulated cultures that proliferated in response to rTNF-alpha. B cells from three of ten patients proliferated spontaneously and proliferation was further enhanced in two patients by rTNF-alpha. TNF binding assays gave a value of approximately 390 to 1,400 binding sites/cell for TNF and a dissociation constant (kd) of approximately 60 pmol/L. These data indicate that rTNF-alpha, in contrast to its cytotoxic/cytostatic effects, can also induce proliferation of tumor cells.

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