scholarly journals Abnormal function of the bone marrow microenvironment in chronic myelogenous leukemia: role of malignant stromal macrophages

Blood ◽  
1995 ◽  
Vol 85 (12) ◽  
pp. 3636-3645 ◽  
Author(s):  
R Bhatia ◽  
PB McGlave ◽  
GW Dewald ◽  
BR Blazar ◽  
CM Verfaillie
Keyword(s):  
Bone Marrow ◽  
Chronic Myelogenous Leukemia ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Interleukin 1 ◽  
Relative Proportion ◽  
Bone Marrow Microenvironment ◽  
Myelogenous Leukemia ◽  
Necrosis Factor Alpha

The bone marrow microenvironment supports and regulates the proliferation and differentiation of hematopoietic cells. Dysregulated hematopoiesis in chronic myelogenous leukemia (CML) is caused, at least in part, by abnormalities in CML hematopoietic progenitors leading to altered interactions with the marrow microenvironment. The role of the microenvironment itself in CML has not been well characterized. We examined the capacity of CML stroma to support the growth of long-term culture-initiating cells (LTC-IC) obtained from normal and CML marrow. The growth of normal LTC-IC on CML stroma was significantly reduced compared with normal stroma. This did not appear to be related to abnormal production of soluble factors by CML stroma because normal LTC-IC grew equally well in Transwells above CML stroma as in Transwells above normal stroma. In addition, CML and normal stromal supernatants contained similar quantities of both growth-stimulatory (granulocyte colony-stimulating factor (CSF), interleukin-6, stem cell factor, granulocyte-macrophage CSF, and interleukin-1 beta) and growth-inhibitory cytokines (transforming growth factor-beta, macrophage inflammatory protein-1 alpha, and tumor necrosis factor-alpha). The relative proportion of different cell types in CML and normal stroma was similar. However, polymerase chain reaction and fluorescence in situ hybridization studies showed the presence of bcr-abl-positivo cells in CML stroma, which were CD14+ stromal macrophages. To assess the effect of these malignant macrophages on stromal function, CML and normal stromal cells were separated by fluorescence-activated cell sorting into stromal mesenchymal cell (CD14-) and macrophage (CD14+) populations. CML and normal CD14-cells supported the growth of normal LTC-IC equally well. However, the addition of CML macrophages to normal or CML CD14-mesenchymal cells resulted in impaired progenitor support. This finding indicates that the abnormal function of CML bone marrow stroma is related to the presence of malignant macrophages. In contrast to normal LTC-IC, the growth of CML LTC-IC on allogeneic CML stromal layers was not impaired and was significantly better than that of normal LTC-IC cocultured with the same CML stromal layers. These studies demonstrate that, in addition to abnormalities in CML progenitors themselves, abnormalities in the CML marrow microenvironment related to the presence of malignant stromal macrophages may contribute to the selective expansion of leukemic progenitors and suppression of normal hematopoiesis in CML.

scholarly journals Cytokine production by primary bone marrow megakaryocytes

Blood ◽  
1994 ◽  
Vol 84 (12) ◽  
pp. 4151-4156 ◽  
Author(s):  
S Jiang ◽  
JD Levine ◽  
Y Fu ◽  
B Deng ◽  
R London ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Interleukin 1 ◽  
Human Bone ◽  
Human Bone Marrow ◽  
Tnf Alpha ◽  
Necrosis Factor Alpha ◽  
Gm Csf

Primary human bone marrow megakaryocytes were studied for their ability to express and release cytokines potentially relevant to their proliferation and/or differentiation. The purity of the bone marrow megakaryocytes was assessed by morphologic and immunocytochemical criteria. Unstimulated marrow megakaryocytes constitutively expressed genes for interleukin-1 beta (IL-1 beta), IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNF-alpha), by the polymerase chain reaction (PCR) and Northern blot analysis. At the protein level, megakaryocytes secreted significant amounts of IL-1 beta (53.6 +/- 3.6 pg/mL), IL-6 (57.6 +/- 15.6 pg/mL), and GM-CSF (24 +/- 4 pg/mL) but not TNF-alpha. Exposure of human marrow megakaryocytes to IL-1 beta increased the levels of IL-6 (87.3 +/- 2.3 pg/mL) detected in the culture supernatants. Transforming growth factor- beta was also able to stimulate IL-6, IL-1 beta, and GM-CSF secretion, but was less potent than stimulation with phorbol-12-myristate-13- acetate (PMA). The secreted cytokines acted additively to maintain and increase the number of colony-forming unit-megakaryocytes colonies (approximately 35%). These studies demonstrate the production of multiple cytokines by isolated human bone marrow megakaryocytes constitutively or stimulated in vitro. The capacity of human megakaryocytes to synthesize several cytokines known to modulate hematopoietic cells supports the concept that there may be an autocrine mechanism operative in the regulation of megakaryocytopoiesis.

Parathyroid Hormone-Induced Modulation of the Bone Marrow Microenvironment Inhibits the Development of Murine Chronic Myelogenous-Leukemia-Like Disease

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 937-937
Author(s):  
Daniela S. Krause ◽  
Sanon Lezeau ◽  
Michael Hurley ◽  
Ernestina Schipani ◽  
David T. Scadden
Keyword(s):  
Bone Marrow ◽  
Parathyroid Hormone ◽  
Chronic Myelogenous Leukemia ◽  
Lymphoblastic Leukemia ◽  
Osteoclast Differentiation ◽  
Phosphodiesterase Inhibitor ◽  
Bone Marrow Microenvironment ◽  
Myelogenous Leukemia ◽  
Prolonged Survival

Abstract Abstract 937 The role of the bone marrow microenvironment, and in particular of osteoblastic cells, for normal hematopoiesis has recently been described. However, the role of elements of the bone marrow microenvironment on the initiation, maintenance or progression of leukemia is less clear. To test the influence of activated osteoblasts on the progression of chronic myelogenous leukemia (CML) we used the well-described murine retroviral transduction/transplantation model of BCR-ABL1-induced CML-like disease and mice with osteoblastic cell-specific constitutive activation of the parathyroid-hormone (PTH) receptor (PPR mice) as recipients. Compared to wildtype (wt) littermate control mice PPR mice had significantly prolonged survival (p=0.002) and reduced leukemic mortality with splenic leukemopoiesis contributing to leukemic fatality. Analysis of distinct proviral integration sites in splenic tissue by Southern blotting showed no difference in engraftment of viral clones in wt versus PPR mice. Survival of PPR recipients in the BCR-ABL1-induced model of B-cell acute lymphoblastic leukemia using non-5-fluorouracil-treated donor bone marrow was also significantly prolonged compared to wt mice (p=0.0004). However, a leukemogenic allele known to result in acute myeloid leukemia (AML), MLL-AF9, led to more rapid death in the PPR recipients compared with their wt counterparts arguing that the prolongation of survival in the BCR-ABL1-induced diseases was oncogene-specific. In-vitro assays including the Whitlock-Witte assay to test the role of PPR stroma or a cobblestone colony formation assay in osteogenic medium revealed no difference in the growth of plated BCR-ABL1+ or BCR-ABL1- B-lymphoid progenitors or lin- c-kit+ Sca-1+ cells on wt versus PPR stroma, respectively. In vivo, treatment of mice with the phosphodiesterase inhibitor forskolin, which increases intracellular cyclic adenosine monophosphate (cAMP) levels, similar to increased signaling from the PTH receptor, did not lead to prolonged survival in the murine model of CML-like disease. Prior splenectomy of wt, as well as PPR recipients of BCR-ABL1-induced CML-like disease did not significantly prolong survival, but drastically reduced the efficiency of induction of CML-like disease with the great majority of wt and PPR animals succumbing to non-CML causes. Secondary transplantation of CML-like disease from bone marrow or spleen from a wt or PPR microenvironment revealed, firstly, less efficient induction of secondary disease in wt recipients of PPR bone marrow compared to wt bone marrow and, secondly, superiority of CML-induction in secondary recipients of spleen compared to bone marrow from a PPR microenvironment. In order to test for an osteoblast-extrinsic cause of the prolonged survival of PPR recipients in the CML-model and to test for the role of bone remodeling, wt and PPR recipients of BCR-ABL1-transduced bone marrow were treated with saline or osteoprotegerin, an inhibitor of osteoclast differentiation and proliferation. Surprisingly, 100% of PPR and wt control mice succumbed to CML-like disease sooner than the control mice treated with saline. Additionally, continuous infusion of human PTH(1-34) into wt mice with BCR-ABL1-induced CML-like disease by minipump led to prolonged survival compared to saline-treated animals arguing that PTH may be an intervention beneficial in human CML. This, to our knowledge, represents first evidence that modulation of the bone marrow microenvironment may improve the outcome in leukemia. Disclosures: Scadden: Fate Therapeutics: Consultancy, Equity Ownership, Patents & Royalties.

scholarly journals Role of endocannabinoid CB1 receptors in Streptozotocin-induced uninephrectomised Wistar rats in diabetic nephropathy

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Jayarami Reddy Medapati ◽  
Deepthi Rapaka ◽  
Veera Raghavulu Bitra ◽  
Santhosh Kumar Ranajit ◽  
Girija Sankar Guntuku ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Morphological Changes ◽  
Serum Levels ◽  
Cb1 Receptors ◽  
Protective Effects ◽  
Renal Hypertrophy ◽  
Necrosis Factor Alpha

Abstract Background The endocannabinoid CB1 receptor is known to have protective effects in kidney disease. The aim of the present study is to evaluate the potential agonistic and antagonistic actions and to determine the renoprotective potential of CB1 receptors in diabetic nephropathy. The present work investigates the possible role of CB1 receptors in the pathogenesis of diabetes-induced nephropathy. Streptozotocin (STZ) (55 mg/kg, i.p., once) is administered to uninephrectomised rats for induction of experimental diabetes mellitus. The CB1 agonist (oleamide) and CB1 antagonist (AM6545) treatment were initiated in diabetic rats after 1 week of STZ administration and were given for 24 weeks. Results The progress in diabetic nephropathy is estimated biochemically by measuring serum creatinine (1.28±0.03) (p < 0.005), blood urea nitrogen (67.6± 2.10) (p < 0.001), urinary microprotein (74.62± 3.47) (p < 0.005) and urinary albuminuria (28.31±1.17) (p < 0.0001). Renal inflammation was assessed by estimating serum levels of tumor necrosis factor alpha (75.69±1.51) (p < 0.001) and transforming growth factor beta (8.73±0.31) (p < 0.001). Renal morphological changes were assessed by estimating renal hypertrophy (7.38± 0.26) (p < 0.005) and renal collagen content (10.42± 0.48) (p < 0.001). Conclusions From the above findings, it can be said that diabetes-induced nephropathy may be associated with overexpression of CB1 receptors and blockade of CB1 receptors might be beneficial in ameliorating the diabetes-induced nephropathy. Graphical abstract

scholarly journals Local and systemic influence of toxic levels of airborne ozone on the inflammatory response in rats

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Małgorzata Chmielewska-Krzesińska ◽  
Krzysztof Wąsowicz
Keyword(s):  
Inflammatory Response ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Interleukin 1 ◽  
Interleukin 10 ◽  
Necrosis Factor Alpha ◽  
Genes Expression ◽  
Factor Alpha ◽  
Anti Inflammatory ◽  
Necrosis Factor

Abstract Introduction Ozone is not harmful itself; however, it directly oxidises biomolecules and produces radical-dependent cytotoxicity. Exposure to ozone is by inhalation and therefore the lungs develop the main anti-inflammatory response, while ozone has an indirect impact on the other organs. This study investigated the local and systemic effects of the ozone-associated inflammatory response. Material and Methods Three groups each of 5 Wistar Han rats aged 6 months were exposed for 2h to airborne ozone at 0.5 ppm and a fourth identical group were unexposed controls. Sacrifice was at 3h after exposure for control rats and one experimental group and at 24 h and 48 h for the others. Lung and liver samples were evaluated for changes in expression of transforming growth factor beta 1, anti-inflammatory interleukin 10, pro-inflammatory tumour necrosis factor alpha and interleukin 1 beta and two nuclear factor kappa-light-chain-enhancer of B cells subunit genes. Total RNA was isolated from the samples in spin columns and cDNA was synthesised in an RT-PCR. Expression levels were compared to those of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and analysed statistically. Results All variables changed non-linearly over time comparing experimental groups to the control. Conspicuous expression changes in the subunit genes and cytokines were observed in both evaluated organs. Conclusion Locally and systemically, inflammation responses to ozone inhalation include regulation of certain genes’ expression. The mechanisms are unalike in lungs and liver but ozone exerts a similar effect in both organs. A broader range of variables influential on ozone response should be studied in the future.

Kinetics of cytokine expression during healing of acute colitis in mice

1996 ◽  
Vol 271 (1) ◽  
pp. G130-G136 ◽  
Author(s):  
L. A. Dieleman ◽  
C. O. Elson ◽  
G. S. Tennyson ◽  
K. W. Beagley
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Interleukin 1 ◽  
Rna Extraction ◽  
Cytokine Expression ◽  
Tnf Alpha ◽  
Colonic Injury ◽  
Necrosis Factor Alpha ◽  
Inflammatory Protein ◽  
Kinetics Of

The mechanisms of wound healing in the gut are poorly understood but are mediated by cytokines in other tissues. In this study we wanted to determine which cytokines were expressed after nonspecific colonic injury, the kinetics of that expression, and how cytokine expression correlated with tissue histology. At 0, 4, 8, 12, 24, 48, and 72 h after intrarectal administration of 3% acetic acid to C3H/HeJ mice, their colons were removed for histology, organ culture, and RNA extraction. Cytokine mRNA expression for various cytokines was assessed by reverse transcriptase-polymerase chain reaction with primers specific for each cytokine. Cytokine production in organ cultures was measured with bioassays. Shortly after colonic injury and during colonic regeneration, proinflammatory cytokines such as interleukin-1 beta (IL-1 beta), IL-6, tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein (MIP), and transforming growth factor-beta (TGF-beta) were expressed. In contrast, expression of T cell-derived cytokines was not detected at any time point. Cytokines such as IL-1 beta, IL-6, IL-10, TNF-alpha, and MIP-1 are important mediators of tissue repair and restitution after nonspecific colonic injury and may subserve a similar role in human colitis.

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