An intrinsic thyrotropin-mediated pathway of TNF-α production by bone marrow cells

Blood ◽  
2003 ◽  
Vol 101 (1) ◽  
pp. 119-123 ◽  
Author(s):  
Heuy-Ching Wang ◽  
Jolene Dragoo ◽  
Qin Zhou ◽  
John R. Klein
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Hematopoietic Cells ◽  
Thyroid Stimulating Hormone ◽  
Appreciable Change ◽  
Tnf Α ◽  
Factor Α ◽  
Inductive Signal ◽  
Necrosis Factor

Abstract Recent studies have identified a role for thyroid-stimulating hormone (TSH; ie, thyrotropin) as an inductive signal for tumor necrosis factor-α (TNF-α) secretion by bone marrow (BM) cells, although the features of that activation pathway have not been defined. Using intracellular TSH staining and enzyme-linked immunoassay for detection of secreted TSH, we demonstrate that TSH synthesis in BM cells occurs within CD45+ (leukocyte common antigen) hematopoietic cells and that the majority of that activity resides in a component of CD11b+ BM cells that are not mature T cells, B cells, or Thy-1+ cells in the BM. Conversely, TSH-responsive BM cells defined by expression of TSH receptor (TSHR) using flow cytometry were selectively associated with a nonerythroid CD11b− lymphocyte precursor population. In vitro culture of magnetic-activated cell sorted CD11b− and CD11b+ cells with titrated amounts of purified TSH resulted in significantly higher levels of TNF-α secretion from CD11b− BM cells compared to non-TSH–treated cells, with no appreciable change in TNF-α production from CD11b+cells. These findings are the first to demonstrate TSH production by BM hematopoietic cells, and they demonstrate that TSH may be involved in the regulation of TNF-α by CD11b− BM cells. They also indicate that TSH-mediated regulation of TNF-α secretion within the BM most likely operates through an intrinsic network of TSH production and use between different types of BM cells, and they suggest that local TSH may be an important homeostatic regulator of hematopoiesis mediated by TNF-α.

Phagocytosis of Co-Developing Megakaryocytic Progenitors by Dendritic Cells in the Culture with Thrombopoietin and Tumor Necrosis Factor-α: Possible Role in Hemophagocytic Syndrome.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3082-3082
Author(s):  
Kenichi Sawada ◽  
Makoto Hirokawa ◽  
Kayo Inaba ◽  
Hiroshi Fukaya ◽  
Yoshinari Kawabata ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Hemophagocytic Syndrome ◽  
Cytokine Production ◽  
Bone Marrow Cells ◽  
Human Cd34 ◽  
Cd34 Cells ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor ◽  
Number Of Cells

Abstract Background. Tumor necrosis factor-α (TNF-α) and thrombopoietin (TPO) have been shown to sustain differentiation and proliferation of CD34+ cells toward dendritic cells (DCs) in the presence of multi-acting cytokines. We hypothesized that co-stimulation of TPO and TNF-α generate megakaryocytic progenitors and DCs together from human CD34+ cells and that interaction of these cells may provide a physiological and/or a pathological role of DCs in megakaryopoiesis. Materials and Methods. Highly purified human CD34+ cells were cultured with TPO, with or without TNF-α, in plasma-depleted medium and induced to undergo megakaryocytic differentiation. We enumerated megakaryocytic progenitor cells using the specific markers CD41, CD42b, and CD61, and DCs using CD4, CD11c, CD80, CD83, CD86, and CD123. The character and roles of co-developing non-megakaryocytic cells in the presence of TNF-α were analyzed by fluorescence-activated cell sorter, enzyme immunohistochemistry, confocal microscopy, and autologous mixed lymphocyte reaction. Cytokine production was assessed using a cytometric bead array system. Results. When CD34+ cells were cultured for 7 days in the presence of TPO, the generated cells predominantly expressed CD41 (95±2%), CD42b (54±12%), and CD61 (96±2%), while rarely expressing CD11c (1.6±1.3%), CD80 (0.1±0.1%), CD83 (0.8±0.6%), or CD86 (3.3±1.9%). The addition of TNF-α significantly decreased the number of cells expressing CD41 (3.0±0.6%), CD42b (3.3±1.0%), or CD61 (3.2±0.9%), but did not affect the number of total cells. In the presence of TNF-α, the generated cells expressed major histocompatibility complex (MHC) class I (100%) plus MHC class II (100%). A substantial number of cells became positive for CD11c (37±1%), and even co-stimulatory molecules such as CD80 (2.4±1.9%), CD83 (8±4%), and CD86 (18±7%). Immature CD11c+ DCs were physically associated with apoptotic and CD61+ cells and capable of endocytosing CD61+ cells. Most of the CD11c+ cells co-expressed the c-mpl TPO receptor, CD4, and CD123 and about one half of CD11c+ cells co-expressed CD86. The DCs generated by TNF-α and TPO, but not those by TNF-α alone, facilitated autologous T cell proliferation in some extent, although cytokine production from activated T cells were low. We also confirmed engulfment of CD61+ cells and their fragment by CD11c+ cells in bone marrow cells from patients with hemophagocytic syndromes. Conclusions. This is the first report showing that in the presence of TNF-α, the non-megakaryocytic cells with typical feature of DCs are co-generated from human CD34+ cells during megakaryocytic differentiation by TPO. The CD4+ CD11c+ CD123+ DCs physically associates with and phagocytose developing or dying immature megakaryocytic cells. Similar phenomenon showing engulfment of CD61+ fragment by CD11c+ cells was also observed in bone marrow cells from patients with hemophagocytic syndrome. Therefore, it may be conceivable that DCs with phagocytic activity during the development in bone marrow may play a crucial role in the maintenance of tolerance for self-substances derived from hematopoietic progenitor cells.

Epinephrine inhibits endotoxin-induced IL-1β production: roles of tumor necrosis factor-α and IL-10

1997 ◽  
Vol 273 (6) ◽  
pp. R1885-R1890 ◽  
Author(s):  
Tom Van Der Poll ◽  
Stephen F. Lowry
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Ex Vivo ◽  
Systemic Infection ◽  
Tnf Α ◽  
Cytokine Tumor Necrosis Factor ◽  
Dose Dependent Decrease ◽  
Factor Α ◽  
Necrosis Factor

Epinephrine has been found to inhibit the production of the proinflammatory cytokine tumor necrosis factor (TNF)-α and to enhance the production of anti-inflammatory cytokine interleukin (IL)-10. To determine the effect of epinephrine on IL-1β production, the following experiments were performed: 1) blood obtained from subjects at 4–21 h after the start of a continuous infusion of epinephrine (30 ng ⋅ kg−1⋅ min−1) produced less IL-1β after ex vivo stimulation with lipopolysaccharide (LPS), compared with blood drawn from subjects infused with saline; 2) in whole blood in vitro, epinephrine caused a dose-dependent decrease in LPS-induced IL-1β production, which was likely mediated via adrenergic receptors; and 3) inhibition of TNF and enhancement of IL-10 both contributed to epinephrine-induced inhibition of IL-1β production. Epinephrine, either endogenously produced or administered as a component of sepsis treatment, may attenuate excessive activity of proinflammatory cytokines early in the course of systemic infection.

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

Blood ◽  
2009 ◽  
Vol 113 (21) ◽  
pp. 5111-5120 ◽  
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.

Nonstressed rat model of acute endotoxemia that unmasks the endotoxin-induced TNF-α response

1999 ◽  
Vol 276 (2) ◽  
pp. H671-H678 ◽  
Author(s):  
David W. A. Beno ◽  
Robert E. Kimura
Keyword(s):  
Rat Model ◽  
Endotoxic Shock ◽  
Stress Hormones ◽  
Tnf Α ◽  
Baseline Concentrations ◽  
Experimental Protocols ◽  
Factor Α ◽  
Necrosis Factor

Previous investigators have demonstrated that the tumor necrosis factor-α (TNF-α) response to endotoxin is inhibited by exogenous corticosterone or catecholamines both in vitro and in vivo, whereas others have reported that surgical and nonsurgical stress increase the endogenous concentrations of these stress-induced hormones. We hypothesized that elevated endogenous stress hormones resultant from experimental protocols attenuated the endotoxin-induced TNF-α response. We used a chronically catheterized rat model to demonstrate that the endotoxin-induced TNF-α response is 10- to 50-fold greater in nonstressed (NS) rats compared with either surgical-stressed (SS, laparotomy) or nonsurgical-stressed (NSS, tail vein injection) models. Compared with the NS group, the SS and NSS groups demonstrated significantly lower mean peak TNF-α responses at 2 mg/kg and 6 μg/kg endotoxin [NS 111.8 ± 6.5 ng/ml and 64.3 ± 5.9 ng/ml, respectively, vs. SS 3.9 ± 1.1 ng/ml ( P < 0.01) and 1.3 ± 0.5 ng/ml ( P < 0.01) or NSS 5.2 ± 3.2 ng/ml ( P < 0.01) at 6 μg/kg]. Similarly, baseline concentrations of corticosterone and catecholamines were significantly lower in the NSS group [84.5 ± 16.5 ng/ml and 199.8 ± 26.2 pg/ml, respectively, vs. SS group 257.2 ± 35.7 ng/ml ( P< 0.01) and 467.5 ± 52.2 pg/ml ( P < 0.01) or NS group 168.6 ± 14.4 ng/ml ( P < 0.01) and 1,109.9 ± 140.7 pg/ml ( P < 0.01)]. These findings suggest that the surgical and nonsurgical stress inherent in experimental protocols increases baseline stress hormones, masking the endotoxin-induced TNF-α response. Subsequent studies of endotoxic shock should control for the effects of protocol-induced stress and should measure and report baseline concentrations of corticosterone and catecholamines.

scholarly journals Tumor Necrosis Factor α Stimulates Osteoclast Differentiation by a Mechanism Independent of the Odf/Rankl–Rank Interaction

2000 ◽  
Vol 191 (2) ◽  
pp. 275-286 ◽  
Author(s):  
Kanichiro Kobayashi ◽  
Naoyuki Takahashi ◽  
Eijiro Jimi ◽  
Nobuyuki Udagawa ◽  
Masamichi Takami ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Osteoclast Differentiation ◽  
Osteoclast Formation ◽  
Fab Fragment ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Osteoclast differentiation factor (ODF, also called RANKL/TRANCE/OPGL) stimulates the differentiation of osteoclast progenitors of the monocyte/macrophage lineage into osteoclasts in the presence of macrophage colony-stimulating factor (M-CSF, also called CSF-1). When mouse bone marrow cells were cultured with M-CSF, M-CSF–dependent bone marrow macrophages (M-BMMφ) appeared within 3 d. Tartrate-resistant acid phosphatase–positive osteoclasts were also formed when M-BMMφ were further cultured for 3 d with mouse tumor necrosis factor α (TNF-α) in the presence of M-CSF. Osteoclast formation induced by TNF-α was inhibited by the addition of respective antibodies against TNF receptor 1 (TNFR1) or TNFR2, but not by osteoclastogenesis inhibitory factor (OCIF, also called OPG, a decoy receptor of ODF/RANKL), nor the Fab fragment of anti–RANK (ODF/RANKL receptor) antibody. Experiments using M-BMMφ prepared from TNFR1- or TNFR2-deficient mice showed that both TNFR1- and TNFR2-induced signals were important for osteoclast formation induced by TNF-α. Osteoclasts induced by TNF-α formed resorption pits on dentine slices only in the presence of IL-1α. These results demonstrate that TNF-α stimulates osteoclast differentiation in the presence of M-CSF through a mechanism independent of the ODF/RANKL–RANK system. TNF-α together with IL-1α may play an important role in bone resorption of inflammatory bone diseases.

scholarly journals Production of cytokines by bone marrow cells obtained from patients with multiple myeloma

Blood ◽  
1989 ◽  
Vol 74 (4) ◽  
pp. 1266-1273 ◽  
Author(s):  
A Lichtenstein ◽  
J Berenson ◽  
D Norman ◽  
MP Chang ◽  
A Carlile
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Interleukin 1 ◽  
Interleukin 2 ◽  
In Vitro Production ◽  
Osteolytic Bone Disease ◽  
Vitro Production ◽  
Necrosis Factor

Abstract Previous work with continuously cultured multiple myeloma lines suggested that cytokine production by tumor cells may mediate some of the medical complications of this disease. To further investigate this issue, we assayed freshly obtained bone marrow (BM) cells from myeloma patients for the in vitro production of cytokines and the presence of cytokine RNA. Production of cytokine protein was assessed by bioassays with the aid of specific neutralizing anticytokine antibodies. These assays detected interleukin-1 (IL-1) and tumor necrosis factor (TNF) secretion by myeloma BM cells, which was significantly greater than secretion from similarly processed BM cells of control individuals. In contrast, lymphotoxin and interleukin-2 (IL-2) production could not be detected. The levels of IL-1 and TNF produced in vitro peaked at 24 hours of culture and correlated with stage and the presence (or absence) of extensive osteolytic bone disease. Northern blot analysis demonstrated the presence of IL-1 beta and TNF RNA in uncultured myeloma BM cells but no detectable IL-1 alpha or lymphotoxin RNA. In addition, the amount of cytokine RNA correlated with protein production, being significantly greater in patients' BM cells than in control marrow. These data suggest a role for IL-1 beta and/or TNF in the pathophysiology of multiple myeloma and argue against a role for lymphotoxin or IL-2.

The Augmented Productions of Neopterin and Cytokines from Macrophages/monocytes in vitro

Pteridines ◽  
1996 ◽  
Vol 7 (3) ◽  
pp. 72-76
Author(s):  
Tadashi Lizuka ◽  
Mitsuyo Sasaki ◽  
Hitomi Kamisako ◽  
Ko Oishi ◽  
Shigeru Uemura ◽  
...  
Keyword(s):  
Kawasaki Disease ◽  
Interleukin 1 ◽  
Poly I:C ◽  
Recombinant Interferon ◽  
Preliminary Examination ◽  
Tnf Α ◽  
Ifn Γ ◽  
Factor Α ◽  
Necrosis Factor

Summary In Kawasaki disease patients, increases in excretion of urinary neopterin coincided with fever and monocytosis in peripheral blood. We examined the products of neopterin, tumor necrosis factor-α (TNFα) and Interleukin-1 β (1L-1β) from healthy adult macrophages/monocytes (Mφ>/M), after stimulation with several activators to obtain some understanding of Kawasaki disease. Upon stimulation with either lipopolysaccharide (LPS) or polyinosinate-polycytidylate (Poly I:C), the Mφ/M released neopterin and pyogenic products (TNF-α or 1L-1β). The release of neopterin was eliminated by the addition of the anti-interferon-y antibody. The production of both TNF-α, 1L-1β and neopterin from Mφ/M upon stimulation of LPS was augmented in a co-culture with low dose recombinant interferon-y (rIFN-γ). Upon stimulation with rIFN-γ alone, however, the Mφ/M released neopterin but not the pyogenic products. A preliminary examination failed to detect. any difference in the response of the Mφ/M in adults annd children after stimulation with LPS. We concluded that some endotoxins could trigger the onset of Kawasaki disease and that endogenous IFN-γ can play an important role in the abnormality of Kawasaki disease patients

TNF-α induced bronchial vasoconstriction

2000 ◽  
Vol 279 (3) ◽  
pp. H946-H951 ◽  
Author(s):  
Elizabeth M. Wagner
Keyword(s):  
Bronchial Artery ◽  
Autologous Blood ◽  
Inflammatory Status ◽  
Tnf Α ◽  
In Vitro Systems ◽  
Essential Function ◽  
Factor Α ◽  
Necrosis Factor ◽  
Airways Inflammation

The pro-inflammatory characteristics of tumor necrosis factor-α (TNF-α) have been extensively characterized in in vitro systems. Furthermore, this cytokine has been shown to play a pivotal role in airways inflammation in asthma. Since the airway vasculature also performs an essential function in inflammatory cell transit to the airways, experiments were performed to determine the effects of TNF-α on bronchial vascular resistance (BVR). In anesthetized, ventilated sheep, the bronchial artery (BA) was cannulated and perfused with autologous blood. BVR was defined as inflow pressure/flow and averaged 6.3 ± 0.2 mmHg · ml−1 · min−1 (±SE) for the 25 sheep studied. Recombinant human TNF-α (10 μg for 20 or 40 min) infused directly into the BA resulted in a significant decrease in BVR to 87% of baseline ( P < 0.05). This vasodilation was followed by a reversal of tone by 120 min and a sustained increase in BVR to 126% of baseline ( P < 0.05). Since others have shown TNF-α caused coronary vasoconstriction through endothelial release of endothelin-1 (ET-1), an ET-1 antagonist was used to block bronchial vasoconstriction. BQ-123, a selective ETA receptor antagonist, was delivered to the bronchial vasculature prior to TNF-α challenge. Attenuation of bronchial vasoconstriction was observed at 120 min ( P < 0.03). Thus TNF-α causes bronchial vasoconstriction by the secondary release of ET-1. Although TNF-α exerts pro-inflammatory actions on most cells of the airways, vasoactive properties of this cytokine likely further contribute to the inflammatory status of the airways.

scholarly journals Analysis of Bone Marrow-derived Mesenchymal Stem Cell Kinetics after Short-term Stimulation with Tumor Necrosis Factor-α (TNF-α)

2019 ◽  
Vol 28 (2) ◽  
pp. 99-108 ◽  
Author(s):  
Mio Naritani ◽  
Miho Inoue ◽  
Resmi Raju ◽  
Mayu Miyagi ◽  
Masamitsu Oshima ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Cell Kinetics ◽  
Short Term ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Impaired Granulocytic Differentiation In Vitro in Hematopoietic Cells Lacking Retinoic Acid Receptors α1 and γ

Blood ◽  
1998 ◽  
Vol 92 (2) ◽  
pp. 607-615 ◽  
Author(s):  
Jean Labrecque ◽  
Deborah Allan ◽  
Pierre Chambon ◽  
Norman N. Iscove ◽  
David Lohnes ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Retinoic Acid ◽  
Bone Marrow Cells ◽  
Hematopoietic Cells ◽  
Hematopoietic Cell ◽  
Retinoic Acid Receptors ◽  
Wild Type ◽  
Granulocytic Differentiation ◽  
Marrow Cells

Transcripts for the retinoic acid receptors (RARs) α1, α2, γ1, and γ2 were found in the granulocytic lineage (Gr-1+cells) through semiquantitative polymerase chain reaction (PCR) analysis. The screening of single cell cDNA libraries derived from hematopoietic progenitors also showed the presence of RARα and, to a lesser extent, RARγ transcripts in committed granulocyte (colony-forming unit-granulocyte [CFU-G]) or granulocyte-macrophage (CFU-GM) colony-forming cells. The contribution of RARα1 and γ to hematopoietic cell differentiation was therefore investigated in mice bearing targeted disruption of either one or both of these loci. Because RARγ and RARα1γ compound null mutants die shortly after birth, bone marrow cells were collected from fetuses at 18.5 days postcoitum (dpc) and evaluated for growth and differentiation in culture in the presence of Steel factor (SF), interleukin-3 (IL-3), and erythropoietin (Epo). The frequency of colony-forming cells from bone marrow populations derived from RARα1/γ double null mice was not significantly different from that of RARγ or RARα1 single nulls or from wild-type controls. In addition, the distribution of erythroid, granulocyte, and macrophage colonies was comparable between hematopoietic cells from all groups, suggesting that lineage commitment was not affected by the lack of RARα1 and/or RARγ. Colony cells were then harvested individually and evaluated by morphologic criteria. While terminal granulocyte differentiation was evident in wild-type cells and colonies from either single null mutant, colonies derived from RARα1−/−γ−/− bone marrow populations were blocked at the myelocyte and, to a lesser extent, at the metamyelocyte stages, whereas erythroid and macrophage differentiation was not affected. Together, these results indicate that both RARα1 and γ are required for terminal maturation in the granulocytic lineage in vitro, but appear to be dispensable for the early stages of hematopoietic cell development. Our results raise the possibility that in acute promyelocytic leukemia (APL), the different RARα fusion proteins cause differentiation arrest at a stage when further maturation requires not only RARα, but also RARγ. Finally, bone marrow cells appear to differentiate normally in vivo, suggesting an effective compensation mechanism in the RARα1/γ double null mice.

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