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Glioblastoma multiforme (GBM) comprises several molecular subtypes, including proneural GBM. Most therapeutic approaches targeting glioma cells have failed. An alternative strategy is to target cells in the glioma microenvironment, such [...]

Am J Physiol Renal Physiol 298: F133-F141, 2010. First published November 11, 2009; doi: 10.1152/ajprenal.00400.2009.--Histone deacetylase (HDAC) regulates gene expression by modifying chromatin structure. Although changes in the expression and activities of HDAC may affect the course of kidney disease, the role of HDAC in tubulointerstitial injury has not been explored. We therefore investigated the alterations in HDAC expression and determined the effects of HDAC inhibition on the tubulointerstitial injury induced by unilateral ureteral obstruction. The induction of HDAC1 and HDAC2, accompanied by a decrease in histone acetylation was observed in kidneys injured by ureteral obstruction. Immunohistochemical analysis revealed that HDAC1 and HDAC2 were induced in renal tubular cells. Treatment with an HDAC inhibitor, trichostatin A (TSA), attenuated macrophage infiltration and fibrotic changes in tubulointerstitial injury induced by ureteral obstruction. The induction of colony-stimulating factor-1 (CSF-1), a chemokine known to be involved in macrophage infiltration in tubulointerstitial injury, was reduced in injured kidneys from mice treated with TSA. TSA, valproate, and the knockdown of HDAC1 or HDAC2 significantly reduced CSF-1 induced by TNF-[alpha] in renal tubular cells. These results suggest that tubular HDAC1 and HDAC2, induced in response to injury, may contribute to the induction of CSF-1 and the initiation of macrophage infiltration and profibrotic responses. These findings suggest a potential of HDAC inhibition therapy aimed at reducing inflammation and fibrosis in tubulointerstitial injury. epigenetic; chemokine; ureteral obstruction

Bone metabolism results from a balance between osteoclast-driven bone resorption and osteoblast-mediated bone formation. Diseases such as periodontitis and rheumatoid arthritis are characterized by increased bone destruction due to enhanced osteoclastogenesis (1,2). Here we report that interferon regulatory factor-8 (IRF-8), a transcription factor expressed in immune cells, is a key regulatory molecule for osteoclastogenesis. IRF-8 expression in osteoclast precursors was downregulated during the initial phase of osteoclast differentiation induced by receptor activator of nuclear factor-[kappa]]B ligand (RANKL), which is encoded by the Tnfsf11 gene. Mice deficient in Irf8 showed severe osteoporosis, owing to increased numbers of osteoclasts, and also showed enhanced bone destruction after lipopolysaccharide (LPS) administration. [Irf8.sup.-/-] osteoclast precursors underwent increased osteoclastogenesis in response to RANKL and tumor necrosis factor-[alpha] (TNF-[alpha]). IRF-8 suppressed osteoclastogenesis by inhibiting the function and expression of nuclear factor of activated T cells c1 (NFATc1). Our results show that IRF-8 inhibits osteoclast formation under physiological and pathological conditions and suggest a model where downregulation of inhibitory factors such as IRF-8 contributes to RANKL-mediated osteoclastogenesis., Osteoclasts are multinucleated giant cells derived from the monocyte and macrophage lineage. Their differentiation is triggered by RANKL in the presence of macrophage colony-stimulating factor (M-CSF, encoded by the Csf1 [...]

We have previously shown that a granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-15 (IL-15) 'fusokine' (GIFT15) exerts immune suppression via aberrant signaling through the IL-15 receptor on lymphomyeloid cells. We show here that ex vivo GIFT15 treatment of mouse splenocytes generates suppressive regulatory cells of B cell ontogeny (hereafter called GIFT15 [[B.sub.reg] cells). Arising from [CD19.sup.+] B cells, GIFT15 [B.sup.reg] cells express major histocompatibility complex class I (MHCI) and MHCII, surface IgM and IgD, and secrete IL-10, akin to previously described B10 and T2-MZP [[B.sub.reg] cells, but lose expression of the transcription factor PAX5, coupled to upregulation of CD138 and reciprocal suppression of CD19. Mice with experimental autoimmune encephalomyelitis went into complete remission after intravenous infusion of GIFT15 [[B.sub.reg] cells paralleled by suppressed neuroinflammation. The clinical effect was abolished when GIFT15 [[B.sub.reg] cells were derived from m[micro]MT (lacking B cells), MHCII--knockout, signal transducer and activator of transcription-6 (STAT-6)-knockout, IL-10-- knockout or allogeneic splenocytes, consistent with a pivotal role for MHCII and IL-10 by sygeneic B cells for the observed therapeutic effect. We propose that autologous GIFT15 [[B.sub.reg] cells may serve as a new treatment for autoimmune ailments., A well established model of multiple sclerosis, experimental autoimmune encephalitis (EAE), is a chronic inflammatory disease of the central nervous system characterized by the activation of the immune system against [...]

Pain is one of the most severe and debilitating symptoms associated with several forms of cancer (1, 2). Various types of carcinomas and sarcomas metastasize to skeletal bones and cause spontaneous bone pain and hyperalgesia, which is accompanied by bone degradation and remodeling of peripheral nerves (2). Despite recent advances, the molecular mechanisms underlying the development and maintenance of cancer-evoked pain are not well understood (2). Several types of non-hematopoietic tumors secrete hematopoietic colony-stimulating factors that act on myeloid cells (3) and tumor cells (4). Here we report that receptors and signaling mediators of granulocyte- and granulocyte-macrophage colony-stimulating factors (G-CSF and GM-CSF) (3) are also functionally expressed on sensory nerves. GM-CSF sensitized nerves to mechanical stimuli in vitro and in vivo, potentiated CGRP release and caused sprouting of sensory nerve endings in the skin. Interruption of G-CSF and GM-CSF signaling in vivo led to reduced tumor growth and nerve remodeling, and abrogated bone cancer pain. The key significance of GM-CSF signaling in sensory neurons was revealed by an attenuation of tumor-evoked pain following a sensory nerve-specific knockdown of GM-CSF receptors. These results show that G-CSF and GM-CSF are important in tumor-nerve interactions and suggest that their receptors on primary afferent nerve fibers constitute potential therapeutic targets in cancer pain., Pancreatic biopsy samples from patients with pancreatic adenocarcinoma showed significantly higher levels of G-CSF and GM-CSF than were seen in pancreatic samples from healthy donors (Fig. 1a; P o 0.05). [...]

Two types of blast colonies can be stimulated to develop in semisolid agar cultures of murine bone marrow cells. Typically, these are either multicentric colonies stimulated by stem cell factor (SCF) plus interleukin-6 (IL-6) or dispersed colonies stimulated by Fit3 ligand (FL) plus IL-6. Both types of blast colony-forming ceils (BL-CFCs) can generate large numbers of lineage-committed granulocyte-macrophage progenitor cells and exhibit some capacity for self-generation and the formation of eosinophil and megakaryocyte progenitor cells. However, the two populations of BL-CFCs are largely distinct and partially separable by fluorescence-activated cell sorting and are distinguished by differing capacity to form granulocyte-committed progeny. Both types of BL-CFCs can generate dendritic cells and small numbers of lymphocytes but the FL-responsive BL-CFCs have a greater capacity to form both B and T lymphocytes. Both types of blast colonies offer remarkable opportunities to analyze muitilineage commitment at a clonal level in vitro. blast colonies | T and B lymphocytes

Impaired host defense post-bone marrow transplant (BMT) is related to overproduction of prostaglandin [E.sub.2] (PG[E.sub.2]) by alveolar macrophages (AMs). We show AMs post-BMT overproduce granulocyte-macrophage colony-stimulating factor (GM-CSF), whereas GM-CSF in lung homogenates is impaired both at baseline and in response to infection post-BMT. Homeostatic regulation of GM-CSF may occur by hematopoietic/ structural cell cross talk. To determine whether AM overproduction of GM-CSF influenced immunosuppression post-BMT, we compared mice that received BMT from wild-type donors (control BMT) or mice that received BMT from GM-CSF-/- donors (GM-CSF-/BMT) with untransplanted mice. GM-CSF-/- BMT mice were less susceptible to pneumonia with Pseudomonas aeruginosa compared with control BMT mice and showed antibacterial responses equal to or better than untransplanted mice. GM-CSF-/- BMT AMs displayed normal phagocytosis and a trend toward enhanced bacterial killing. Surprisingly, AMs from GM-CSF-/- BMT mice overproduced PG[E.sub.2], but expression of the inhibitory E[P.sub.2] receptor was diminished. As a consequence of decreased E[P.sub.2] receptor expression, we found diminished accumulation of cAMP in response to PG[E.sub.2] stimulation in GM-CSF-/- BMT AMs compared with control BMT AMs. In addition, GM-CSF-/- BMT AMs retained cysteinyl leukotriene production and normal TNF-[alpha] response compared with AMs from control BMT mice. GM-CSF-/- BMT neutrophils also showed improved bacterial killing. Although genetic ablation of GM-CSF in hematopoietic cells post-BMT improved host defense, transplantation of wild-type bone marrow into GM-CSF-/- recipients demonstrated that parenchymal cell-derived GM-CSF is necessary for effective innate immune responses post-BMT. These results highlight the complex regulation of GM-CSF and innate immunity post-BMT. lung; Pseudomonas aeruginosa; eicosanoid; neutrophil

The distribution of fertile polyps, and the functional variations of polyps within sea-pen colonies, were investigated in Virgularia juncea, a species inhabiting shallow waters in the Penghu Islands, west of Taiwan. This gonochoristic species started gametogenesis between July and September, and mature gametes were broadcast in late summer the following year. Fertile pinnae and their constituent polyps were located in the middle region of the rachis; the upper and lower regions were infertile. Within the fertile regions, fecundity per centimeter decreased linearly toward the tips of the colonies. Abundant zooxanthellae were found in the upper part of the rachis; algal densities decreased down the axis of the colonies, and no algae were present in the lower part. New pinnae were generated only at the basal part of the rachis, They moved upward in relative position with growth of the colonies. These young pinnae near the peduncle were small and infertile. With time, they became fertile and started to harbor a few zooxanthellae. The old pinnae at the upper part of the rachis were large and infertile and contained numerous zooxanthellae. The tips of the colonies were often damaged, and the bare axial rods there were often fragile and could be easily broken of. The developmental gradient of pinnae (and their constituent polyps) along the axes of the colonies, coupled with the environmental gradient within a sea-pen colony, facilitates the functional differentiation within the rachis that may be an adaptation for inhabiting the interface between the water column and the sediment., Introduction The Pennatulacea, to which all sea pens belong, are unique among anthozoan orders in that all members live both above and below the sediment. Their peduncles are buried in [...]

Significant alterations in pulmonary surfactant homeostasis are brought about by the ablation of GM-CSF signaling, leading to accumulation of surfactant lipids and proteins in the alveolar spaces and tissues of the lung. Further, interruption of this signaling pathway by attacking GM-CSF gene or its receptor by auto-antibodies results in pathogenesis of pulmonary alveolar proteinosis.

Galactosialidosis (GS) is a human neurodegenerative disease caused by a deficiency of lysosomal protective protein/cathepsin A (PPCA). The GS mouse model resembles the severe human condition, resulting in nephropathy, ataxia, and premature death. To rescue the disease phenotype, GS mice were transplanted with bone marrow from transgenic mice overexpressing human PPCA specifically in monocytes/macrophages under the control of the colony stimulating factor-1 receptor promoter. Transgenic macrophages infiltrated and resided in all organs and expressed PPCA at high levels. Correction occurred in hematopoietic tissues and nonhematopoietic organs, including the central nervous system. PPCA-expressing perivascular and leptomeningeal macrophages were detected throughout the brain of recipient mice, although some neuronal cells, such as Purkinje cells, continued to show storage and died. GS mice crossed into the transgenic background reflected the outcome of bone marrow-transplanted mice, but the course of neuronal degeneration was delayed in this model. These studies present definite evidence that macrophages alone can provide a source of corrective enzyme for visceral organs and may be beneficial for neuronal correction if expression levels are sufficient.

The peroxisome proliferator-activated receptor [Gamma] (PPAR[Gamma]) is a ligand-dependent transcription factor that has been demonstrated to regulate fat cell development and glucose homeostasis. PPAR[Gamma] is also expressed in a subset of macrophages and negatively regulates the expression of several proinflammatory genes in response to natural and synthetic ligands. We here demonstrate that PPAR[Gamma] is expressed in macrophage foam cells of human atherosclerotic lesions, in a pattern that is highly correlated with that of oxidation-specific epitopes. Oxidized low density lipoprotein (oxLDL) and macrophage colony-stimulating factor, which are known to be present in atherosclerotic lesions, stimulated PPAR[Gamma] expression in primary macrophages and monocytic cell lines. PPAR[Gamma] mRNA expression was also induced in primary macrophages and THP-1 monocytic leukemia cells by the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA). Inhibition of protein kinase C blocked the induction of PPAR[Gamma] expression by TPA, but not by oxLDL, suggesting that more than one signaling pathway regulates PPAR[Gamma] expression in macrophages. TPA induced the expression of PPAR[Gamma] in RAW 264.7 macrophages by increasing transcription from the PPAR[Gamma]1 and PPAR[Gamma]3 promoters. In concert, these observations provide insights into the regulation of PPAR[Gamma] expression in activated macrophages and raise the possibility that PPAR[Gamma] ligands may influence the progression of atherosclerosis.

[Beta]-chemokines play an important role in the development of immunologic reactions. Macrophages are major [Beta]-chemokine-producing cells during T-cell directed, delayed-type hypersensitivity reactions in tissues, and have been reported to be important producers of [Beta]-chemokines in the lymph nodes of HIV-1-infected individuals. However, the physiological signals responsible for inducing macrophages to produce [Beta]-chemokines have not been established. Two soluble T cell products, interferon-[Gamma] and granulocyte-macrophage colony stimulating factor, were added to cultured macrophages, but failed to stimulate the production of macrophage inflammatory protein-1[Alpha] and -1[Beta]; regulated upon activation, normal T cell expressed and secreted (RANTES); or monocyte chemoattractant protein-1. Instead, direct cell-cell contact between macrophages and cells engineered to express CD40L (also known as CD154) resulted in the production of large amounts of macrophage inflammatory protein-1[Alpha] and -1[Beta], and RANTES (all ligands for CCR5), and monocyte chemoattractant protein-1 (a ligand for CCR2). Supernatants from CD40L-stimulated macrophages protected CD[4.sup.+] T cells from infection by a nonsyncytium-inducing strain of HIV-1 (which uses CCR5 as a coreceptor). These results have implications for granulomatous diseases, and conditions such as atherosclerosis and multiple sclerosis, where CD40L-bearing cells have been found in the macrophage-rich lesions where [Beta]-chemokines are being produced. Overall, these findings define a pathway linking the specific recognition of antigen by T cells to the production of [Beta]-chemokines by macrophages. This pathway may play a role in anti-HIV-1 immunity and the development of immunologic reactions or lesions.

I. DESCRIPTION OF MONONUCLEAR PHAGOCYTE SYSTEM: CELL TYPES AND DIFFERENTIATION STAGES Cells of the macrophage (MΦ) lineage or mononuclear phagocyte system (MPS) (34, 35, 131) are more complex than other [...]

The role of anionic phospholipids on structurally analogous growth factors was investigated by Fluorescence spectroscopy, isothermal titration calorimetry and other analytical methods. The results showed that the phospholipids interact with the recombinant granulocyte colony-stimulating factor to stimulate neutrophil proliferation and activity. They also conferred stability to the growth factors.

Cyclic AMP (cAMP) stimulates cell cycle arrest in mid-G1 phase in macrophages, by inhibiting the mitogenic effects of colony-stimulating factor 1 (CSF-1). The cdk-activating kinase (CAK) does not phosphorylate cyclin-dependent kinase 4 (cdk4), which forms complexes with cyclin D1 that accumulate in growth arrested cells. Antibody precipitation enables the extraction of active CAK from lysates of cAMP-treated cells, indicating that it is not the direct target of inhibition. Cdk inhibitor p27Kip1 levels in cAMP-treated cells are more and its immunodepletion from inhibitory lysates reestablishes CAK-mediated cdk4 activation. Kip1 inhibits CAK phosphorylation and the activation of the holo-enzyme by binding to cyclin D-cdk4.

Granulocyte/macrophage colony-stimulating factor-deficient mice reveal no significant hematopoiesis perturbation up to 12 weeks of age, but develop abnormal lungs with beta lymphocyte infiltration. The abnormal lung growth is similar to human alveolar proteinosis disease and is not required to maintain blood, spleen and narrow hematopoietic cells.

Granulocyte/macrophage-colony stimulating factor (GM-CSF) expression is regulated by the modulation of mRNA half-life, which is in turn regulated by AU-rich sequences. The role of the AU-rich regionin regulating this process was further explored. The results showed that at least three proteins are involved in recognizing the 3' untranslated region of the mouse GM-CSF mRNA. Binding assays showed that the region recognized by these proteins are limited to the AU-rich sequences. Phorbol ester treatment did not change the levels of these proteins, suggesting that the control point of mRNA degradation is at the level of enzyme activity.

Hemopoietic regulators are mostly glycoproteins with polypeptide molecular masses of 14-21 kDa exhibiting variable amino acid sequence despite the similarity in functional activity. Hemopoietic regulators serve as activators of mature blood cell formation. Colony stimulating factors (CSF) initiate the production of granulocytes and monocytes while erythropoietin act in the formation of erythrocytes. Macrophage-CSF, multipotential-CSF, interleukins 1 and 2 were also identified as hemopoietic regulators.

TWO TYPES OF WHITE BLOOD CELLS, THE NEUTROPHILIC granulocytes and monocytes (or their tissue derivatives, the macrophages), are of importance in resistance to infections; abnormally low numbers of granulocytes are [...]

Hemopoietic precursor cells, or stem cells, develop into mature blood cells, including both red cells and white blood cells. The development, growth, and survival of the precursor cells depend on factors or molecules known as colony stimulating factors (CSFs). It has been shown that CSFs promote cell survival by the suppression of apoptosis, or self-destruction of the cells. Apoptosis is characterized at the cellular level by: degradation of DNA, deoxyribose nucleic acid, the material of genes; condensation of chromatin, the material from which chromosomes (the structural units which contain the genes of the cell) are formed; and loss of the microvilli, or tiny projections of the plasma membrane of the cell. Apoptosis is an active process which, in many systems, is dependent on the synthesis of proteins involved in cell death. This study demonstrates that apoptosis is suppressed by a number of the CSFs including IL-3 (interleukin-3), GM-CSF (granulocyte-macrophage colony stimulating factor), and G-CSF (granulocyte colony stimulating factor). If these factors are removed from the medium in which the cells grow, the cells undergo apoptosis. Therefore, CSFs regulate the survival of precursor cells. CSFs can be used to regulate or stimulate normal hematopoiesis in patients whose precursor cells, or stem cells, have been destroyed by various conditions such as radiation. The removal or inhibition of CSFs can also as be used to suppress cell growth in various cancers affecting precursor blood cells. (Consumer Summary produced by Reliance Medical Information, Inc.)

Byline: A. Bouchama (1), B. Khan (2), W. Djazmati (1), K. Shukri (1) Keywords: Key words G-CSF; GM-CSF; Neutropenia; Sepsis; Intensive care Abstract: Objective: To assess whether adjunct hematopoietic colony-stimulating factor (H-CSF) accelerates neutrophil recovery and improves survival. Design: A retrospective study. Setting: Medical/surgical intensive care unit (ICU). Patients: 30 neutropenic patients admitted to the ICU and treated with H-CSF. Controls were the preceding 30 neutropenic patients not treated with H-CSF. Measurements and results: Patient admission characteristics were reviewed. Endpoints were neutrophil recovery ( > 1.0 x 10.sup.9/l), length of ICU stay and survival. Depth and duration of neutropenia (0.267 +- 0.04 x 10.sup.9/l for 12 +- 1.7 days vs 0.293 +- 0.05 x 10.sup.9/l for 15 +- 1.9 days p = 0.67 and 0.21), and the Acute Physiology and Chronic Health Evaluation II and organ system failure scores were similar. Systemic candidiasis was lower in the H-CSF group (20 vs 3 % p > 0.05). In 11 (36.6 %) and 10 (33.3 %) patients neutrophil count recovered ( > 1.0 x 10.sup.9/l) H-CSF did not reduce the duration of neutropenia (7.8 +- 1.4 vs 5.7 +- 1.3 days p = 0.28), the length of ICU stay (7.8 +- 1.1 vs 8.9 +- 1.5 days p = 0.55) or improve survival (23 vs 10 % p = 0.168). Conclusion: H-CSF for treatment of neutropenia in patients admitted to the ICU did not accelerate neutrophil recovery or improve survival. Author Affiliation: (1) Medicine Department (MBC 46), King Faisal Specialist Hospital + Research Centre, P. O. Box 3354, Riyadh 11211, Saudi Arabia e-mail: abouchama@hotmail.com Tel. + 966(1)4 42 74 93 Fax + 966(1)4 42 74 99, SA (2) Departments of Biomedical Statistics, King Faisal Specialist Hospital + Research Centre, Riyadh, Saudi Arabia, SA Article note: Received: 4 January 1999 Final revision received: 26 April 1999 Accepted: 26 May 1999

Modular organisms consist of repeated building blocks. An important consequence of modularity may be reflected in the ability of a colony to continually reallocate priority of resource transport among its units in response to stress. Hermatypic corals, the main organisms constructing tropical reefs, are prone to damage by a multitude of agents. Since colonization of lesions by competitors is a potent threat to colonial organisms, fast recovery is an important component of colony survival. Previous regeneration studies have claimed that the energy requirements of this essential process are fueled only by the polyps directly bordering the injured area. This 'localized regeneration hypothesis' rejects the necessity for wide colony integration during regeneration and sees no advantage to large colony size. The objective of the present study was to test an alternative regeneration hypothesis that argues, in contrast, that injury repair (i.e., closure of lesions by newly formed tissues) in corals may require extended colony integration (i.e., internal translocation of resources from sites of acquisition to sites of maximal demand). To test our hypothesis we examined: (1) the relationship between colony size and percentage recovery of lesions differing in size and shape; and (2) the effect of different sized lesions on the fecundity of polyps located at increasing distances from the lesion site. Both experiments were conducted on the common, spherically shaped coral Favia favus in the Red Sea near Eilat, Israel. The relatively small lesions ([is less than] 1 [cm.sup.2]) were the only ones to support the localized regeneration hypothesis, since their recovery was unaffected by colony size. However, the two larger lesion types (approximate sizes of 2 [cm.sup.2] and 3 [cm.sup.2]) confirmed the importance of large colony size for achieving fast recovery. In the second experiment we found that small lesions, repeated monthly, caused only a localized reduction in fecundity, while larger monthly repeated lesions caused significant reductions in fecundity up to a distance of 15 cm away from their site. Both experiments indicate that regeneration from injury may require an extended magnitude of energy integration throughout the colony, and that the extent of this integration is regulated by the colony in accordance with lesion characteristics. It is also concluded that in long-lived organisms such as corals, there is a priority of energy allocation to recovery rather than to reproduction. Our findings reveal the existence of injury thresholds within a colony that determine energy allocation and intra-colonial translocation of energy products toward regions of maximal demand. We suggest that such injury thresholds may characterize many other coral species and that colony integration during stress is a basic life-preserving ability and one of the most important advantages of clonal and colonial organisms. Key words: artificial lesions; clonal organisms; colony integration; coral regeneration; energy allocation; Favia favus; fecundity; Israel; Red Sea.

Increasing membrane-bound MCSF does not enhance OPGL-driven osteoclastogenesis from marrow cells. Am J Physiol Endocrinol Metab 280: E103-E111, 2001.--Macrophage colony-stimulating factor (MCSF) and osteoprotegerin ligand (OPGL), both produced by osteoblasts/ stromal cells, are essential factors for osteoclastogenesis. Whether local MCSF levels regulate the amount of osteoclast formation is unclear. Two culture systems, ST-2 and Chinese hamster ovary-membrane-bound MCSF (CHO-mMCSF)-Tet-OFF cells, were used to study the role of mMCSF in osteoclast formation. Cells from bone marrow (BMM) or spleen were cultured with soluble OPGL on glutaraldehyde-fixed cell layers; osteoclasts formed after 7 days. Osteoclast number was proportional to the amount of soluble OPGL added. In contrast, varying mMCSF levels in the ST-2 or CHO-mMCSF-Tet-OFF cell layers, respectively by variable plating or by addition of doxycycline, did not affect BMM osteoclastogenesis: 20-450 U of mMCSF per well generated similar osteoclast numbers. In contrast, spleen cells were resistant to mMCSF: osteoclastogenesis required [is greater than or equal to] 250 U per well and further increased as mMCSF rose higher. Our results demonstrate that osteoclast formation in the local bone environment is dominated by OPGL. Increasing mMCSF above basal levels does not further enhance osteoclast formation from BMMs, indicating that mMCSF does not play a dominant regulatory role in the bone marrow. tetracycline regulation; osteoclast differentiation factor; TRANCE; colony stimulating factor-1; bone marrow

The constant regeneration of the blood system during hematopoiesis requires tightly controlled lineage decisions of hematopoietic progenitor cells (HPCs). Because of technical limitations, differentiation of individual HPCs could not previously be analyzed continuously. It was therefore disputed whether cell-extrinsic cytokines can instruct HPC lineage choice or only allow survival of cells that are already lineage-restricted. Here, we used bioimaging approaches that allow the continuous long-term observation of individual differentiating mouse HPCs. We demonstrate that the physiological cytokines, macrophage colony-stimulating factor and granulocyte colony-stimulating factor, can instruct hematopoietic lineage choice.

Human granulocyte-macrophage colony-stimulating factor (GM-CSF) is a glycoprotein hormone that stimulates the growth of hematopoietic progenitor cells and enhances the functional activity of mature myeloid effector cells. Granuloycte-macrophage colony-stimulating factor was administered to eight patients with severe aplastic anemia in an attempt to restore adequate hematopoiesis. Profound decreases in serum cholesterol concentrations were observed during GM-CSF therapy that were not dependent on changes in the patients' peripheral blood cell counts. Serum cholesterol levels decreased by an average of 37% during treatment, reaching levels of less than 4.40 mmol/L in all patients. Serum cholesterol concentrations returned to baseline in all patients after discontinuation of GM-CSF therapy. Treatment with GM-CSF prominently alters cholesterol homeostasis in vivo, although the mechanism of this effect is unknown. Our results suggest that GM-CSF may be potentially useful in the treatment of hypercholesterolemia and, possibly, in the prevention and treatment of atherosclerosis.