Bifunctional effects of tumor necrosis factor alpha (TNF alpha) on the growth of mature and primitive human hematopoietic progenitor cells: involvement of p55 and p75 TNF receptors

Abstract

Tumor necrosis factor alpha (TNF alpha) has previously been reported to have both inhibitory and stimulatory effects on hematopoietic progenitor cells. Specifically, TNF alpha has been proposed to stimulate early hematopoiesis in humans. In the present study we show that TNF alpha, in a dose-dependent fashion, can potently inhibit the growth of primitive high proliferative potential colony-forming cells (HPP-CFCs) stimulated by multiple cytokine combinations. Using agonistic antibodies to the p55 and p75 TNF receptors or TNF alpha mutants specific for either of the two TNF receptors, we show that both receptors can mediate this inhibition. In contrast, the potent stimulation of interleukin-3 (IL-3) plus granulocyte-macrophage colony- stimulating factor (GM-CSF) induced HPP-CFC colony formation observed at low concentrations of TNF alpha (2 ng/mL) was only a p55-mediated event. Moreover, the stimulatory effects of TNF alpha on GM-CSF or IL-3- induced colony formation, as well as the inhibition of G-CSF-induced colony growth, were also exclusively signaled through the p55 TNF receptor. Taken together, our results suggest that the inhibitory effects of TNF alpha on primitive bone marrow progenitor cells are mediated through both p55 and p75 TNF receptors, whereas the p55 receptor exclusively mediates the bidirectional effects on more mature, single factor-responsive bone marrow progenitor cells as well as stimulation of IL-3 plus GM-CSF-induced HPP-CFC colony growth.

TNF/TNFR axis promotes pyrin inflammasome activation and distinctly modulates pyrin inflammasomopathy

“…Granulocyte-derived TNF has been recently shown to promote vascular remodeling and hematopoietic recovery during BM transplantation (67). The specific role of TNFR1 signaling in neutrophilia in Mefv V726A/V726A mice is consistent with previous studies that show that TNFR1, but not TNFR2, synergizes with GM-CSF to promote granulocyte differentiation (49,68). Additionally, it was interesting that neutrophilia in Mefv V726A/V726A mice lacking TNF signaling was reduced despite significant levels of neutrophilia-promoting mediators, such as G-CSF, KC, and IL-17, in these mice ( Figure 3D).…”

“…Additionally, it was interesting that neutrophilia in Mefv V726A/V726A mice lacking TNF signaling was reduced despite significant levels of neutrophilia-promoting mediators, such as G-CSF, KC, and IL-17, in these mice ( Figure 3D). However, TNF can modulate hematopoiesis (49,68), expression of adhesion molecules (69,70), and neutrophil chemotaxis and apoptosis (71,72), and it is likely that neutrophilia in FMF mice is affected by these functions of TNF signaling.…”

An unbalanced monocyte macrophage polarization in the bone marrow microenvironment of patients with poor graft function after allogeneic haematopoietic stem cell transplantation

“…Fanconi anaemia patients are often found to overproduce TNF‐α, which may directly affect HSC function by impairing HSC survival, homing and proliferation or indirectly change the BM microenvironment, thereby contributing to disease progression (Du et al , ). In agreement with this, previous studies have demonstrated that TNF‐α can negatively regulate the growth of murine and human haematopoietic progenitors, including HSCs (Broxmeyer et al , ; Backx et al , ; Rusten et al , ; Zhang et al , ). Our experimental evidence demonstrated that the TNF‐α levels were much higher in the supernatants of BM CD34 + cells cocultured with PGF BM MФs than in those cocultured with GGF BM MФs.…”

Leukocytosis in obese individuals: possible link in patients with unexplained persistent neutrophilia

“…In this respect, human adipose tissue was found to produce and release pro‐inflammatory cytokines and chemokines including interleukin‐6 (9), tumor necrosis factor‐ α (10–12), interleukin‐1 (13), and interleukin‐8 (14). These cytokines and chemokines can induce neutrophilia via demargination of intravascular neutrophils, acceleration of bone marrow neutrophil release or enhancement of bone marrow granulopoiesis (15–19). Furthermore, leptin the anti‐obesity hormone, mostly produced in adipose tissue was shown to stimulate stem cells and produce granulocyte–macrophage colonies (20, 21).…”