Tumor necrosis factor restricts hematopoietic stem cell activity in mice: involvement of two distinct receptors

Whereas maintenance of hematopoietic stem cells (HSCs) is a requisite for life, uncontrolled expansion of HSCs might enhance the propensity for leukemic transformation. Accordingly, HSC numbers are tightly regulated. The identification of physical cellular HSC niches has underscored the importance of extrinsic regulators of HSC homeostasis. However, whereas extrinsic positive regulators of HSCs have been identified, opposing extrinsic repressors of HSC expansion in vivo have yet to be described. Like many other acute and chronic inflammatory diseases, bone marrow (BM) failure syndromes are associated with tumor necrosis factor-α (TNF) overexpression. However, the in vivo relevance of TNF in the regulation of HSCs has remained unclear. Of considerable relevance for normal hematopoiesis and in particular BM failure syndromes, we herein demonstrate that TNF is a cell-extrinsic and potent endogenous suppressor of normal HSC activity in vivo in mice. These effects of TNF involve two distinct TNF receptors.

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Strategies to Target ADAM17 in Disease: From Its Discovery to the iRhom Revolution

Molecules ◽

10.3390/molecules26040944 ◽

2021 ◽

Vol 26 (4) ◽

pp. 944

Author(s):

Matteo Calligaris ◽

Doretta Cuffaro ◽

Simone Bonelli ◽

Donatella Pia Spanò ◽

Armando Rossello ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Inflammatory Diseases ◽

Structural Similarity ◽

Selective Inhibition ◽

In Vivo Models ◽

Factor Α ◽

Major Drug ◽

Necrosis Factor

For decades, disintegrin and metalloproteinase 17 (ADAM17) has been the object of deep investigation. Since its discovery as the tumor necrosis factor convertase, it has been considered a major drug target, especially in the context of inflammatory diseases and cancer. Nevertheless, the development of drugs targeting ADAM17 has been harder than expected. This has generally been due to its multifunctionality, with over 80 different transmembrane proteins other than tumor necrosis factor α (TNF) being released by ADAM17, and its structural similarity to other metalloproteinases. This review provides an overview of the different roles of ADAM17 in disease and the effects of its ablation in a number of in vivo models of pathological conditions. Furthermore, here, we comprehensively encompass the approaches that have been developed to accomplish ADAM17 selective inhibition, from the newest non-zinc-binding ADAM17 synthetic inhibitors to the exploitation of iRhom2 to specifically target ADAM17 in immune cells.

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In Vivo and in Vitro Evidence for the Involvement of Tumor Necrosis Factor-α in the Induction of Leptin by Lipopolysaccharide*

Endocrinology ◽

10.1210/endo.139.5.6012 ◽

1998 ◽

Vol 139 (5) ◽

pp. 2278-2283 ◽

Cited By ~ 66

Author(s):

Brian N. Finck ◽

Keith W. Kelley ◽

Robert Dantzer ◽

Rodney W. Johnson

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Factor Α ◽

Necrosis Factor

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Ectopic HOXB4 overcomes the inhibitory effect of tumor necrosis factor-α on Fanconi anemia hematopoietic stem and progenitor cells

Blood ◽

10.1182/blood-2008-09-180224 ◽

2009 ◽

Vol 113 (21) ◽

pp. 5111-5120 ◽

Cited By ~ 16

Author(s):

Michael D. Milsom ◽

Bernhard Schiedlmeier ◽

Jeff Bailey ◽

Mi-Ok Kim ◽

Dandan Li ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Fanconi Anemia ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Ectopic Expression ◽

Hematopoietic Stem ◽

Tnf Α ◽

Factor Α ◽

Necrosis Factor

AbstractEctopic delivery of HOXB4 elicits the expansion of engrafting hematopoietic stem cells (HSCs). We hypothesized that inhibition of tumor necrosis factor-α (TNF-α) signaling may be central to the self-renewal signature of HOXB4. Because HSCs derived from Fanconi anemia (FA) knockout mice are hypersensitive to TNF-α, we studied Fancc−/− HSCs to determine the physiologic effects of HOXB4 on TNF-α sensitivity and the relationship of these effects to the engraftment defect of FA HSCs. Overexpression of HOXB4 reversed the in vitro hypersensitivity to TNF-α of Fancc−/− HSCs and progenitors (P) and partially rescued the engraftment defect of these cells. Coexpression of HOXB4 and the correcting FA-C protein resulted in full correction compared with wild-type (WT) HSCs. Ectopic expression of HOXB4 resulted in a reduction in both apoptosis and reactive oxygen species in Fancc−/− but not WT HSC/P. HOXB4 overexpression was also associated with a significant reduction in surface expression of TNF-α receptors on Fancc−/− HSC/P. Finally, enhanced engraftment was seen even when HOXB4 was expressed in a time-limited fashion during in vivo reconstitution. Thus, the HOXB4 engraftment signature may be related to its effects on TNF-α signaling, and this pathway may be a molecular target for timed pharmacologic manipulation of HSC during reconstitution.

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Repetitive Injections of Dendritic Cells Matured with Tumor Necrosis Factor α Induce Antigen-specific Protection of Mice from Autoimmunity

Journal of Experimental Medicine ◽

10.1084/jem.20011341 ◽

2001 ◽

Vol 195 (1) ◽

pp. 15-22 ◽

Cited By ~ 388

Author(s):

Mauritius Menges ◽

Susanne Rößner ◽

Constanze Voigtländer ◽

Heike Schindler ◽

Nicole A. Kukutsch ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Cell Immunity ◽

Tnf Α ◽

Factor Α ◽

Necrosis Factor

Mature dendritic cells (DCs) are believed to induce T cell immunity, whereas immature DCs induce T cell tolerance. Here we describe that injections of DCs matured with tumor necrosis factor (TNF)-α (TNF/DCs) induce antigen-specific protection from experimental autoimmune encephalomyelitis (EAE) in mice. Maturation by TNF-α induced high levels of major histocompatibility complex class II and costimulatory molecules on DCs, but they remained weak producers of proinflammatory cytokines. One injection of such TNF/DCs pulsed with auto-antigenic peptide ameliorated the disease score of EAE. This could not be observed with immature DCs or DCs matured with lipopolysaccharide (LPS) plus anti-CD40. Three consecutive injections of peptide-pulsed TNF/DCs derived from wild-type led to the induction of peptide-specific predominantly interleukin (IL)-10–producing CD4+ T cells and complete protection from EAE. Blocking of IL-10 in vivo could only partially restore the susceptibility to EAE, suggesting an important but not exclusive role of IL-10 for EAE prevention. Notably, the protection was peptide specific, as TNF/DCs pulsed with unrelated peptide could not prevent EAE. In conclusion, this study describes that stimulation by TNF-α results in incompletely matured DCs (semi-mature DCs) which induce peptide-specific IL-10–producing T cells in vivo and prevent EAE.

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Estriol sensitizes rat Kupffer cells via gut-derived endotoxin

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1999.277.3.g671 ◽

1999 ◽

Vol 277 (3) ◽

pp. G671-G677 ◽

Cited By ~ 8

Author(s):

Nobuyuki Enomoto ◽

Shunhei Yamashina ◽

Peter Schemmer ◽

Chantal A. Rivera ◽

Blair U. Bradford ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Kupffer Cells ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Sublethal Dose ◽

Intracellular Ca ◽

Serum Transaminases ◽

Factor Α ◽

Necrosis Factor

The relationship between gender and alcohol-induced liver disease is complex; however, endotoxin is most likely involved. Recently, it was reported that estriol activated Kupffer cells by upregulation of the endotoxin receptor CD14. Therefore, the purpose of this work was to study how estriol sensitizes Kupffer cells. Rats were given estriol (20 mg/kg ip), and Kupffer cells were isolated 24 h later. After addition of lipopolysaccharide (LPS), intracellular Ca2+ concentration was measured using a microspectrofluorometer with the fluorescent indicator fura 2, and tumor necrosis factor-α was measured by ELISA. CD14 was evaluated by Western analysis. One-half of the rats given estriol intraperitoneally 24 h before an injection of a sublethal dose of LPS (5 mg/kg) died within 24 h, whereas none of the control rats died. Mortality was prevented totally by sterilization of the gut with antibiotics. A similar pattern was obtained with liver histology and serum transaminases. Translocation of horseradish peroxidase was increased about threefold in gut segments by treatment with estriol. This increase was not altered by treatment with nonabsorbable antibiotics. On the other hand, endotoxin levels were increased to 60–70 pg/ml in plasma of rats treated with estriol. As expected, this increase was prevented (<20 pg/ml) by antibiotics. In isolated Kupffer cells, LPS-induced increases in intracellular Ca2+ concentration, tumor necrosis factor-α production, and CD14 were increased, as previously reported. All these phenomena were blocked by antibiotics. Therefore, it is concluded that estriol treatment in vivo sensitizes Kupffer cells to LPS via mechanisms dependent on increases in CD14. This is most likely due to elevated portal blood endotoxin caused by increased gut permeability.

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