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Abstract

We studied hemopoiesis in mice deficient by the tumor necrosis factor gene. The total number of cells in long-term bone marrow cultures from these mice 2-fold surpassed that in wild-type and tumor necrosis factor p55 receptor-deficient animals. Increased cell production was related to the absence of tumor necrosis factor expression by hemopoietic precursors. The total cell production by explanted hemopoietic cells from tumor necrosis factor-deficient mice did not depend on the genotype of irradiated stromal sublayer in long-term cell cultures from wild-type mice and animals deficient by tumor necrosis factor or p55 receptor. These results suggest that tumor necrosis factor, but not its p55 receptor, is involved in transduction of signals regulating production of cultured cells. Tumor necrosis factor probably regulates hemopoiesis in long-term bone marrow cultures by initiating apoptosis of hemopoietic cells or inhibiting cell proliferation. Increased cell production probably attests to the absence of one or both effects.

Autocrine Tnf signaling favors malignant cells in myelofibrosis in a Tnfr2-dependent fashion

“…These results are at odds with the attenuation of MPN in a previous study using TNF deficient mice [ 2 ] and suggest that additional, unintended effects, of pan-TNF antagonists may neutralize differences in TNF responses between MF and normal cells [ 2 , 47 ]. Several studies have implicated TNF as a negative regulator of HSCs [ 48 – 50 ]. Conflicting data were reported regarding the requirement for TNFR1 to mediate the suppressive TNF effects on HSCs cultured ex vivo [ 49 , 50 ].…”

“…Several studies have implicated TNF as a negative regulator of HSCs [ 48 – 50 ]. Conflicting data were reported regarding the requirement for TNFR1 to mediate the suppressive TNF effects on HSCs cultured ex vivo [ 49 , 50 ]. In competitive repopulation experiments, both TNFR1 −/− and TNFR2 −/− HSCs were shown to outcompete TNFR WT cells to a similar degree, with a more pronounced advantage for double null cells [ 51 ].…”

Effect of TNF Expression by Stromal Cells on Hemopoietic and Stromal Precursor Cells in Long-Term Bone Marrow Cultures Derived from TNF-Deficient Mice

“…However, an abnormally high level of hemopoiesis during at least the first 20 weeks was described for cultures with TNF-/-sublayer cells and wild type cells [2]. It remained unclear whether expression of TNF by the sublayer cells modified hemopoiesis and whether the absence of autocrine expression of this factor or absence of its expression by the sublayer cells was essential for the status of hemopoietic and stromal precursor cells.…”