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2.
Proc Natl Acad Sci U S A ; 109(41): 16594-9, 2012 Oct 09.
Article in English | MEDLINE | ID: mdl-23012474

ABSTRACT

The bone marrow (BM) is a large, highly active, and responsive tissue. Interestingly, little is known about the impact of colitis on hematopoietic functions. Using dextran sodium sulfate (DSS) to induce colitis in mice, we identified significant changes in the BM. Specifically, cells of the monocytic and granulocytic lineages increased nearly 60% and 80%, respectively. This change would support and promote the large infiltration of the gut with neutrophils and monocytes that are the primary cause of inflammation and tissue damage during colitis. Conversely, the early lineages of B and T cells declined in the marrow and thymus with particularly large losses observed among pre-B and pre-T cells with heightened levels of apoptosis noted among CD4(+)CD8(+) thymocytes from DSS-treated mice. Also noteworthy was the 40% decline in cells of the erythrocytic lineages in the marrow of colitis mice, which undoubtedly contributed to the anemia observed in these mice. The peripheral blood reflected the marrow changes as demonstrated by a 2.6-fold increase in neutrophils, a 60% increase in monocytes, and a decline in the lymphocyte population. Thus, colitis changed the BM in profound ways that parallel the general outcomes of colitis including infiltration of the gut with monocytes and neutrophils, inflammation, and anemia. The data provide important understandings of the full impact of colitis that may lead to unique treatments and therapies.


Subject(s)
Cell Lineage/immunology , Colitis/immunology , Granulocytes/immunology , Monocytes/immunology , Animals , B-Lymphocytes/immunology , B-Lymphocytes/pathology , Bone Marrow Cells/immunology , Bone Marrow Cells/pathology , CD4 Antigens/immunology , CD8 Antigens/immunology , Colitis/chemically induced , Colitis/pathology , Dextran Sulfate , Flow Cytometry , Granulocytes/pathology , Mice , Mice, Inbred C57BL , Monocytes/pathology , Neutrophils/immunology , Neutrophils/pathology , T-Lymphocytes/immunology , T-Lymphocytes/pathology , Thymocytes/immunology , Thymocytes/pathology , Thymus Gland/immunology , Thymus Gland/pathology , Time Factors
4.
Proc Natl Acad Sci U S A ; 109(20): 7622-9, 2012 May 15.
Article in English | MEDLINE | ID: mdl-22538809

ABSTRACT

A rodent model of diet-induced obesity revealed that obesity significantly altered hematopoietic and lymphopoietic functions in the bone marrow and thymus. C57BL/6 mice were fed a mixed high-fat diet (HFD) of 45% fat or 10% fat diet (lean controls) for 180 d. A sustained increase in the numbers of cells found in bone marrow and thymus of HFD mice occurred from day 90 to day 180. However, with the exception of a 10-18% increase in the proportion of lymphocytes, the composition of monocytes, granulocytes, erythrocytes, and mixed progenitor lineages remained normal in the marrow. Likewise, thymuses of HFD mice increased 30-50% in size compared with controls, with analogous increases in thymocyte numbers. The overall thymus cellular composition remained normal. Although increased blood and lymphatic volume in obese mice would play a role in increased hematopoiesis, there were large and disproportionate increases in blood leukocytes of HFD mice, indicating that homeostasis was not maintained. Leptin, which promotes lymphopoiesis and myelopoiesis, reached 100 ng/mL in sera from HFD mice. Moreover, a three- to sixfold increase in adipocytes in marrow resulted in spiked leptin mRNA expression in bones of HFD mice compared with lean controls. Other cytokines and growth factors did not show any increases in obese marrow. The substantial increase in lymphopoietic and hematopoietic processes in HFD mice indicates that the primary tissues are another facet of the immune system dysregulated by obesity, which was perhaps fostered by higher amounts of leptin in marrow and serum.


Subject(s)
Dietary Fats/pharmacology , Hematopoiesis/physiology , Homeostasis/physiology , Lymphopoiesis/physiology , Obesity/physiopathology , Adipocytes/physiology , Animals , Bone Marrow Cells/cytology , Bone Marrow Cells/metabolism , Flow Cytometry , Immunohistochemistry , Leptin/blood , Leukocyte Count , Male , Mice , Mice, Inbred C57BL , Mice, Obese , Obesity/immunology , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Thymus Gland/metabolism
5.
Obesity (Silver Spring) ; 20(5): 1057-65, 2012 May.
Article in English | MEDLINE | ID: mdl-22158006

ABSTRACT

Class III obesity is associated with chronic inflammation and a variety of changes in immune function. Yet surprisingly little was known about the status of neutrophils that represent the first line of immune defense. The aim of this study was to assess key functions of neutrophils from class III obese patients, namely phagocytosis, superoxide production, chemotaxis, and response to endotoxin challenge, and compare their responses with lean controls. Thirty obese patients (BMI 48.8 ± 6.6 kg/m(2)) with comorbidities such as diabetes, hyperlipidemia, high blood pressure, etc. and nine lean (BMI between 20 and 25) subjects were enrolled in the study. Neutrophils from class III obese patients phagocytosed Escherichia coli (E. coli) at similar rates and with adequate numbers of bacteria taken up per cell compared with cells from lean subjects. Neutrophil production of superoxide, which is key to rapid killing of pathogens, showed modest diminution in the class III obese, which increased among patients with BMI >50. Chemotactic activity of neutrophils from class III obese patients was not altered. However, neutrophils from obese subjects showed an increased response to low-dose endotoxin, with concomitant reduced apoptosis and extension of their half-life compared with lean subjects, which suggests possible hyperresponsiveness of these neutrophils. Overall, neutrophil activity was not significantly altered by age, gender, diabetic status, or hyperlipidemia. Collectively, these results suggest that class III obese patients, even with comorbidities, have normal or nearly normal phagocytic, chemotactic, and superoxide generating capacity.


Subject(s)
Neutrophils/immunology , Obesity, Morbid/immunology , Phagocytosis/immunology , Superoxides/metabolism , Adult , Body Mass Index , Diabetes Mellitus/metabolism , Female , Gastric Bypass , Half-Life , Humans , Hyperlipidemias/metabolism , Lipopolysaccharides , Male , Middle Aged , Obesity, Morbid/complications , Obesity, Morbid/surgery , Severity of Illness Index , Superoxides/immunology
6.
Proc Natl Acad Sci U S A ; 105(6): 2017-21, 2008 Feb 12.
Article in English | MEDLINE | ID: mdl-18250302

ABSTRACT

Although leptin is known for its regulation of food intake, it has many emerging roles in immune function. To better define the role of leptin in hematopoietic processes, a leptin-deficient obese mouse (ob/ob) and C57BL/6 lean wild-type controls were compared. Despite their large size and consumption of substantial amounts of nutrients, the ob/ob mice had only 60% as many nucleated cells in their marrow as controls. The greatest impact of leptin deficiency was on the B cell compartment that had 70% fewer cells, reducing the absolute number of pre-B and immature B cells to 21% and 12% of normal, respectively, and indicating a significant reduction in lymphopoiesis in ob/ob mice. Whereas the proportion of myeloids remained nearly normal in the obese mice, they also exhibited a reduction of 40% and 25%, respectively, in absolute numbers of granulocytes and monocytes. Seven days of provision of recombinant leptin promoted substantial lymphopoiesis, increasing the numbers of B cells in the marrow of the obese mice twofold, while doubling and tripling, respectively, the numbers of pre-B and immature B cells. Twelve days of supplementation brought these subpopulations to near-normal proportions. Leptin treatment also facilitated myelopoiesis such that the marrow of the obese mice contained normal numbers of monocytes and granulocytes after 7 days. Taken together, the data support an important role for leptin in sustaining lymphopoiesis and myelopoiesis.


Subject(s)
Hematopoiesis/physiology , Leptin/physiology , Obesity/physiopathology , Animals , Body Weight/physiology , Feeding Behavior/physiology , Leptin/deficiency , Mice , Mice, Inbred C57BL
7.
Proc Natl Acad Sci U S A ; 105(6): 2028-33, 2008 Feb 12.
Article in English | MEDLINE | ID: mdl-18250324

ABSTRACT

Natural glucocorticoids (Gc) produced during stress have profound effects on the immune system. It is well known that Gc induce apoptosis in precursor T and B cells, markedly altering lymphopoiesis. However, it has been noted that marrow myeloid cells expanded both in proportion and absolute numbers in the mouse after Gc exposure. Mice were implanted with a corticosterone (CS) tablet that increased serum Gc and caused atrophied thymuses, both classic signs of activation of the stress axis. Blood neutrophil counts were elevated (4.8x), whereas lymphocyte counts declined. Flow cytometric analysis of the marrow revealed that the phenotypic distribution of the various major classes of cells was shifted by Gc exposure. As expected, marrow lymphocyte numbers declined >40% after 3 days of exposure to Gc. Conversely, in the myeloid compartment, both monocytes and granulocytes increased in number by >40%. Further, all granulocyte developmental stages showed large increases in both total number and percentage of cells. To investigate the functional capacity of mature granulocytes from Gc-treated mice, an improved granulocyte isolation method was developed. Gc exposure had little effect on the ability of granulocytes to produce superoxide or undergo chemotaxis or phagocytose bacteria. These results indicate that Gc treatment shifts bone marrow composition and provides evidence that granulocytes and their progenitors are selectively preserved under stressful conditions without losing function.


Subject(s)
Bone Marrow Cells/cytology , Glucocorticoids/physiology , Granulocytes/cytology , Animals , Bone Marrow Cells/immunology , Cell Separation , Female , Flow Cytometry , Granulocytes/immunology , Mice , Phagocytosis , Thymus Gland/pathology
8.
J Am Coll Nutr ; 24(6): 494-502, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16373946

ABSTRACT

OBJECTIVE: The purpose of this study was to determine the impact of chronic zinc deficiency (ChrZD) on T and B cell lymphopoiesis, myelopoiesis and erythropoiesis in mice. METHODS: Young adult mice were fed a zinc adequate (ZA) or ChrZD synthetic diet for 34, 45, and 50 days. The cellular composition of the thymus and marrow were determined to assess the impact of ChrZD on lymphopoietic and hematopoietic processes using flow cytometry. Body weights, serum zinc and corticosterone (Cs) were monitored. RESULTS: For ChrZD mice growth was reduced 10% and serum zinc declined 15% by d 34 compared to ZA mice. By d 50 a 25% decrease in growth and 70% depression in serum zinc was noted though there was never any significant reduction in diet intake. Corticosterone rose 2.5 fold by d 34 and remained elevated in ChrZD mice indicating induction of the stress axis. At d 34 the thymus of ChrZD mice was normal but by d 50 there was a 50% cell loss and a 10% reduction in the proportion of Pre-T cells. Most importantly there was a 60% increase in Pre-T cells undergoing apoptosis in ChrZD mice. Pro-T, T helper, and T cytolytic populations were more resistant to ChrZD. Bone marrow cellularity and granulocyte, monocyte, and lymphocyte compartments remained unchanged in ChrZD mice. However, the erythroid compartment was reduced by 35% at d 50. CONCLUSIONS: The thymus was the most sensitive primary tissue to ChrZD. By d 50 it had atrophied by 36% with significant loss of Pre-T cells via apoptosis such that T-cell lymphopoiesis was disrupted. Significant reductions were also noted in the erythropoietic population by d 50. Conversely the marrow maintained myelopoiesis and B cell lymphopoiesis for the 50 d period indicating greater ability to survive a chronic zinc deficiency and exposure to Cs. The anemia and T cell lymphopenia associated with ChrZD in both rodents and humans may result from a greater sensitivity of their precursor cells to zinc deficiency and elevated Cs.


Subject(s)
B-Lymphocytes/metabolism , Erythropoiesis/physiology , Lymphopoiesis/physiology , Myelopoiesis/physiology , T-Lymphocytes/metabolism , Zinc/deficiency , Animals , Apoptosis , B-Lymphocytes/immunology , Bone Marrow Cells/immunology , Bone Marrow Cells/pathology , Cell Count , Corticosterone/blood , Erythropoiesis/drug effects , Female , Flow Cytometry , Immunophenotyping , Lymphopoiesis/drug effects , Mice , Myelopoiesis/drug effects , Organ Size , Random Allocation , T-Lymphocytes/immunology , Thymus Gland/cytology , Thymus Gland/immunology , Thymus Gland/pathology , Zinc/pharmacology
9.
J Nutr ; 135(3): 359-62, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15735063

ABSTRACT

Studies of zinc deficiency (ZD) have become important for demonstrating that nutritional imbalances can readily induce programmed cell death (PCD) or apoptosis in a variety of kinds of cells. In mice, ZD caused a 300% increase in the amount of apoptosis among pre T-cells, which was a major cause of thymic atrophy that alters host defense. Embryogenesis was significantly altered in ZD mice due to increased apoptosis in the neural crest, optic, and head regions. Insufficient zinc initiated PCD in hepatocytes, glioma, kidney, monocytes, fibroblasts, and testicular cells, demonstrating the scope of this phenomenon. New forms of cell death continue to emerge. For example, autophagy is initiated by starvation and various nutritional and metabolic imbalances. Autophagy is a form of PCD whereby the cell digests some of its own organelles to provide needed nutrients. Understanding the interplay between these different forms of cell death and nutritional imbalances is very important because of their profound impact on development, growth, immune function, and health.


Subject(s)
Apoptosis/physiology , Cell Death/physiology , Deficiency Diseases/pathology , Zinc/deficiency , Animals , Embryonic Development , Humans , Mice
10.
Annu Rev Nutr ; 24: 277-98, 2004.
Article in English | MEDLINE | ID: mdl-15189122

ABSTRACT

Thymic atrophy, lymphopenia, and compromised cell- and antibody-mediated responses that cause increased rates of infections of longer duration are the immunological hallmarks of zinc deficiency (ZD) in humans and higher animals. As the deficiency advances, a reprogramming of the immune system occurs, beginning with the activation of the stress axis and chronic production of glucocorticoids that accelerate apoptosis among pre-B and -T cells. This reduces lymphopoiesis and causes atrophy of the thymus. In contrast, myelopoiesis is preserved, thereby providing protection for the first line of immune defense or innate immunity. Changes in gene expression for cytokines, DNA repair enzymes, zinc transporters, signaling molecules, etc., suggest that cells of the immune system are attempting to adapt to the stress of suboptimal zinc. Better understanding of the molecular and cellular changes made in response to inadequate zinc should lead to the development of immunotherapeutic interventions.


Subject(s)
Apoptosis/physiology , Immune System/drug effects , Zinc/deficiency , Zinc/pharmacology , Antibody Formation/drug effects , Erythropoiesis , Gene Expression Regulation , Glucocorticoids/biosynthesis , Humans , Immunity, Cellular/drug effects , Myelopoiesis
11.
Article in English | MEDLINE | ID: mdl-12781843

ABSTRACT

The recent detection of perfluorinated compounds (PFCs) in wildlife from even remote locations has spurred interest in the environmental occurrence and effects of these chemicals. While the global distribution of PFCs is increasingly understood, there is still little information available on their effects on wildlife. The amphiphillic nature of PFCs suggests that their effects could be primarily on cell membranes. In this study we measured the effects of PFCs on membrane fluidity and mitochondrial membrane potential using flow cytometry and effects on membrane permeability using cell bioassay procedures (H4IIE, MCF-7, PLHC-1). Of the PFCs tested, only perfluorooctane sulfonic acid (PFOS) increased the permeability of cell membranes to the hydrophobic ligands used. Three PFCs were tested in the membrane fluidity assay: PFOS, perfluorohexane sulfonic acid (PFHS), and perfluorobutane sulfonic acid (PFBS). PFOS increased membrane fluidity in fish leukocytes in a dose-dependent fashion, while PFHS and PFBS had no effect in the concentration range tested. The lowest effective concentrations for the membrane fluidity effects of PFOS were 5-15 mg/l. Effects on mitochondrial membrane potential occurred in the same concentration range as effects on membrane fluidity. This suggests that PFOS effects membrane properties at concentrations below those associated with other adverse effects.


Subject(s)
Alkanesulfonic Acids/toxicity , Environmental Pollutants/toxicity , Fluorocarbons/toxicity , Intracellular Membranes/drug effects , Membrane Fluidity/drug effects , Animals , Biological Assay , Cell Line, Tumor/drug effects , Cell Line, Tumor/enzymology , Cytochrome P-450 CYP1A1/metabolism , Dose-Response Relationship, Drug , Drug Combinations , Fishes , Flow Cytometry , Humans , Intracellular Membranes/physiology , Leukocytes/drug effects , Membrane Fluidity/physiology , Membrane Potentials/drug effects , Membrane Potentials/physiology , Mitochondria/drug effects , Polychlorinated Dibenzodioxins/toxicity , Rats , Transfection
12.
J Nutr ; 133(5): 1403-8, 2003 May.
Article in English | MEDLINE | ID: mdl-12730429

ABSTRACT

The current studies examined whether hematopoiesis in the bone marrow and T-cell development in the thymus were attenuated in young adult A/J mice fed a moderately low protein diet (MPD, 50 g protein/kg) for 15 wk compared with mice fed a control protein diet (CPD, 180 g protein/kg). Flow cytometric analyses using antibodies against CD31 and Ly-6C as well as CD4 and CD8 were performed to identify stem, mixed progenitor, erythroid, lymphoid, granuloid and monocytic compartments in the bone marrow and four thymocyte subsets, respectively. Chronic restriction of young adult mice to MPD neither decreased the cellularity nor altered the distribution of subpopulations in either primary tissue. Subsequently, a new set of mice were provided with CPD and a low protein diet (LPD, 25 g protein/kg). After 5 wk, body and thymus weights in LPD group were reduced 26 and 30%, respectively, which was accompanied by a 505% increase in serum corticosterone. Surprisingly, LPD did not alter the number or distribution of cells in the bone marrow and the percentages of thymocyte subsets, supporting the findings from the MPD group. We conclude that chronic consumption of a marginal protein diet by young adult mice does not disrupt hematopoietic processes.


Subject(s)
Diet, Protein-Restricted , Dietary Proteins/pharmacology , Hematopoiesis/physiology , T-Lymphocytes/immunology , Animals , Body Weight/drug effects , Body Weight/physiology , Corticosterone/blood , Female , Hematopoiesis/drug effects , Metals/blood , Mice , Mice, Inbred A , Serum Albumin/metabolism , T-Lymphocytes/drug effects , Trace Elements/blood
13.
Toxicol Appl Pharmacol ; 187(2): 69-79, 2003 Mar 01.
Article in English | MEDLINE | ID: mdl-12649039

ABSTRACT

Lipopolysaccharide (LPS) and vomitoxin (VT) synergistically induce glucocorticoid- mediated apoptotic cell death in lymphoid tissues of the mouse. Based on the known effects of glucocorticoids, it was hypothesized that the combined exposure to LPS and VT targets immature lymphocyte populations. To test this hypothesis, we quantified the effects of VT and LPS on apoptosis induction in T lymphocyte subsets in thymus and B lymphocyte subsets in Peyer's patches and bone marrow. Flow cytometry revealed that a single dose of LPS (0.1 mg/kg body wt ip) together with VT (12.5 mg/kg body wt po) promoted apoptosis of immature (CD4(-)CD8(-), CD4(+)CD8(+)) and mature (CD4(-)CD8(+)) thymocytes at 12 h with a subsequent reduction of these populations being detectable at 24 h. RU 486, a glucocorticoid receptor antagonist, significantly abrogated apoptosis in CD4(-)CD8(-), CD4(+)CD8(+), and CD4(-)CD8(+) subsets and also prevented loss in cell numbers. In Peyer's patches, mature-B lymphocytes (B220(+)IgM(-)IgD(+)) underwent apoptosis and, in bone marrow, pro/pre-B lymphocytes (B220(+)IgM(-)IgD(-)) and mature-B lymphocytes (B220(+)IgM(-)IgD(+)) underwent apoptosis at 12 h after toxin co- exposure. RU 486 blocked LPS + VT-induced apoptosis of the aforementioned subsets in Peyer patches and bone marrow at 12 h. Taken together, these data suggest that LPS can interact with VT in mice to induce the glucocorticoid-driven apoptotic loss of immature thymocytes and cytotoxic T lymphocytes in thymus, mature-B lymphocytes in Peyer's patch, and pro/pre-B lymphocytes and mature-B lymphocytes in bone marrow in mice.


Subject(s)
Apoptosis/drug effects , B-Lymphocytes/drug effects , Lipopolysaccharides/toxicity , T-Lymphocytes, Cytotoxic/drug effects , Trichothecenes/toxicity , Animals , Apoptosis/immunology , B-Lymphocytes/cytology , B-Lymphocytes/metabolism , Bone Marrow/immunology , Bone Marrow/metabolism , CD4-CD8 Ratio , Crosses, Genetic , Flow Cytometry , Hormone Antagonists/pharmacology , Immunoglobulin M/immunology , Immunoglobulin M/metabolism , Lipopolysaccharides/immunology , Lymphocyte Subsets/drug effects , Lymphocyte Subsets/immunology , Lymphocyte Subsets/metabolism , Male , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Mifepristone/pharmacology , Peyer's Patches/cytology , Peyer's Patches/immunology , Peyer's Patches/metabolism , T-Lymphocytes, Cytotoxic/cytology , T-Lymphocytes, Cytotoxic/metabolism , Thymus Gland/cytology , Thymus Gland/immunology , Thymus Gland/metabolism , Trichothecenes/immunology
14.
J Nutr ; 132(11): 3301-7, 2002 Nov.
Article in English | MEDLINE | ID: mdl-12421843

ABSTRACT

Suboptimal nutriture causes leukopenia, but whether this is related to a modification in hematopoiesis is unknown. A 34-d period of zinc deficiency was used to obtain moderate and severely zinc-deficient (ZD) young adult mice whose bone marrow was evaluated for alterations in hematopoiesis, myelopoiesis and lymphopoiesis by flow cytometry. Expressions of CD31 (PECAM-1) and Ly-6C were used to identify changes in marrow population composition. Identity of marrow cells was confirmed with TER119, CD45R, Ly-6G and CD11b. Cells of the erythroid lineage declined as much as 60% depending on the degree of zinc deficiency, providing new insight into the early observations of clinicians that anemia accompanied ZD in humans. The lymphoid compartment also declined 50-70% with preferential losses among pre-B cells, an underlying cause of the lymphopenia that is a part of ZD, in which loss of pre-B cells was identified by CD43,CD45R, and immunoglobulin M. Conversely, cells of the myeloid lineage increased substantially in the marrow, both in proportion and absolute numbers in all ZD mice. Granulocytic cells increased 40-60%, whereas monocytic cells nearly doubled in ZD mice. These data suggest that there are important adaptations in hematopoietic functions as zinc becomes limiting. In the immune system, the precursors of phagocytic cells, which provide innate immunity, are protected, whereas precursors of lymphocytes, which provide adaptive immunity, are down-regulated. These findings illuminate the unique response of the marrow to a nutritional stress.


Subject(s)
Hematopoiesis , Myelopoiesis , Zinc/deficiency , Animals , B-Lymphocytes/immunology , Biotinylation , Bone Marrow Cells/immunology , Bone Marrow Cells/pathology , Cell Count , Erythropoiesis , Flow Cytometry , Granulocytes/immunology , Immunoglobulin D/analysis , Immunoglobulin M/analysis , Immunophenotyping , Lymphocytes/immunology , Mice , Mice, Inbred A
15.
Toxicol Appl Pharmacol ; 180(1): 43-55, 2002 Apr 01.
Article in English | MEDLINE | ID: mdl-11922776

ABSTRACT

Exposure to bacterial endotoxin (lipopolysaccharide, LPS) is quite common and may increase human susceptibility to chemical-induced tissue injury. The purpose of this study was to identify mechanisms by which LPS potentiates lymphoid tissue depletion in B6C3F1 mice exposed to the common food-borne trichothecene mycotoxin, vomitoxin (VT). As demonstrated by DNA fragmentation and flow cytometric analysis, apoptosis in thymus, Peyer's patches, and bone marrow was marked in mice 12 h after administering Escherichia coli LPS (0.1 mg/kg body wt ip) concurrently with VT (12.5 mg/kg body wt po), whereas apoptosis in control mice or mice treated with either toxin alone was minimal. Based on observed increases in tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6 serum concentrations following LPS and VT cotreatment, the roles of these cytokines in apoptosis potentiation were assessed. Injection with rolipram, an inhibitor of TNF-alpha expression, or use of IL-6 knockout mice was ineffective at impairing thymic apoptosis induction by the toxin cotreatment, suggesting that these cytokines did not mediate LPS potentiation. Toxin cotreatment increased splenic cyclooxygenase-2 mRNA expression, suggesting possible involvement of prostaglandins in apoptosis. However, indomethacin, a broad spectrum inhibitor of cyclooxygenases, failed to block thymus apoptosis. Toxin cotreatment increased serum corticosterone and, furthermore, RU 486, a glucocorticoid receptor antagonist, significantly abrogated apoptosis in thymus, Peyer's patches, and bone marrow following LPS + VT exposure. The results presented herein and the known capacity of glucocorticoids to cause apoptosis indicate that hypothalamic-pituitary-adrenal axis plays a key role in LPS potentiation of trichothecene-induced lymphocyte apoptosis.


Subject(s)
Apoptosis/drug effects , Corticosterone/biosynthesis , Lipopolysaccharides/pharmacology , Lymphocytes/drug effects , Trichothecenes/toxicity , Animals , Corticosterone/blood , Cyclooxygenase 2 , DNA Fragmentation/drug effects , Drug Synergism , Escherichia coli/immunology , Flow Cytometry , Indomethacin/pharmacology , Interleukin-6/blood , Interleukin-6/deficiency , Interleukin-6/genetics , Isoenzymes/biosynthesis , Isoenzymes/genetics , Lymphocytes/pathology , Lymphoid Tissue/drug effects , Lymphoid Tissue/pathology , Male , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Mice, Knockout , Mifepristone/pharmacology , Prostaglandin-Endoperoxide Synthases/biosynthesis , Prostaglandin-Endoperoxide Synthases/genetics , Tumor Necrosis Factor-alpha/analysis , Up-Regulation
16.
Immunology ; 105(1): 111-9, 2002 Jan.
Article in English | MEDLINE | ID: mdl-11849321

ABSTRACT

Exposure to concentrations of glucocorticoids analogous to those produced during stress, trauma and malnutrition had rapid but varying effects on the major classes of cells within the marrow. Corticosterone (CS) was given as a subdermal implant in young mice and generated 60-95 microg CS/dl of blood compared to 5-15 microg CS/dl for sham controls over a period of 36 hr. Within 24 hr CS had caused losses of 30-70% among the early pro-B, pre-B and immature B cells. The pre-B cells were virtually eliminated by 36 hr and the capacity of surviving pro- and pre-B cells to cycle was reduced by 70-80%. Interestingly, the earliest of B cells, the prepro-B cells, showed considerable resistance to CS, being reduced by only 20% at 36 hr. Thus, the pattern of survival within the B-cell compartment paralleled the expression of Bcl-2. At the 36-hr time-point there were no changes in the proportion of progenitor cells, erythroid or monocytic cells, or number of nucleated cells in the marrow. By contrast, 36 hr after exposure to CS there was an increase of 30% in the proportion and absolute number of cells in the granulocytic compartment. Chronic production of CS appears to reprogramme lymphopoiesis and myelopoiesis, perhaps to preserve the first line of immune defence at the expense of the lymphoid branch. Resistance to apoptosis and modifications in the activity of the glucocorticoid receptor and cytokines produced by stromal cells are postulated as targets for CS-driven changes.


Subject(s)
Bone Marrow Cells/pathology , Corticosterone/physiology , Stress, Physiological/pathology , Animals , B-Lymphocytes/pathology , B-Lymphocytes/physiology , Cell Cycle/physiology , Cell Survival , Leukopoiesis/physiology , Male , Mice , Mice, Inbred BALB C , Proto-Oncogene Proteins c-bcl-2/physiology , Stress, Physiological/physiopathology
17.
Cell Immunol ; 220(1): 39-50, 2002 Nov.
Article in English | MEDLINE | ID: mdl-12718938

ABSTRACT

The studies herein demonstrate that Interleukin-7 (IL-7) promotes survival of murine pro- and pre-B cells against stress levels of corticosterone (Cs). In short-term, 16-h, bone marrow cultures IL-7 abrogated Cs-induced apoptosis and cell cycle arrest in pro-B cells by decreasing apoptosis 60% and completely restoring the cell cycle. IL-7 also reduced Cs-induced apoptosis by 36% in pre-B cells and 24% in IgM(+) B cells, but did not restore deficits in the cell cycle. Among pro- and pre- B cells, substantial protection against high, pharmacological, levels of Cs was also provided by IL-7. Interestingly, stem cell factor, while reducing spontaneous apoptosis in pro-B cells, did not protect against Cs-induced death, either alone or with IL-7. In conclusion, IL-7 has potential immunotherapeutic value since it provides substantial protection to pro- and pre-B cells against the adverse effects of Cs.


Subject(s)
Apoptosis/drug effects , B-Lymphocytes/drug effects , Corticosterone/antagonists & inhibitors , Hematopoietic Stem Cells/drug effects , Hormone Antagonists/pharmacology , Interleukin-7/pharmacology , Animals , Antigens, Surface/analysis , Cell Cycle/drug effects , Cell Differentiation , Cells, Cultured/drug effects , Flow Cytometry , Immunoglobulin M/analysis , Male , Mice , Mice, Inbred BALB C , Stem Cell Factor/pharmacology
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