Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To explore the pathogenesis of marrow failure in B-cell type chronic lymphocytic leukemia (B-CLL), we have examined the production of interleukin-6 (IL-6), granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage CSF (GM-CSF) by the adherent cell population of bone marrow (BM) derived from B-CLL patients and their capacity to support hematopoietic cell proliferation. Lipopolysaccharide-stimulated B-CLL stromal cells produced G-CSF and GM-CSF in amounts similar to normal stromal layers, whereas IL-6 production was significantly decreased. Using the blast-colony forming cell assay (BI-CFC) and the classical colony-forming unit granulocyte macrophage (CFU-GM) assay, we found that: (1) marrow stromal cells of B-CLL were able to support only 25% of the BI-CFC growth supported by normal marrow stromal cells; (2) this anomaly was partially corrected by the addition of exogenous IL-6; (3) the colony-stimulating activity (CSA) of the conditioned medium (CM) of B-CLL stromal cells was lower than that of normal CM; (4) that this was the result of the presence of an inhibitor rather that of a growth factor defect; (5) this inhibition could be abrogated by addition of anti-transforming growth factor-beta (TGF-beta) neutralizing antibody; (6) this antibody corrected the deficient colony supportive activity of the B-CLL stromal cells; (7) TGF-beta production by marrow stromal cells was significantly increased in CLL compared with normal; and (8) that this was not caused by the effect of the B-CLL lymphocytes on the stromal cells. It is concluded that this increased TGF-beta production in B-CLL is probably responsible for the decreased IL-6 production by stromal cells and for the inhibiting activity on hematopoietic precursors as well. We hypothesize that TGF-beta generated at a high level by B-CLL marrow stromal cells could play a major role in the pathophysiology of the BM failure seen in advanced stages of B-CLL.
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PMID:Excessive production of transforming growth factor-beta by bone marrow stromal cells in B-cell chronic lymphocytic leukemia inhibits growth of hematopoietic precursors and interleukin-6 production. 769 Dec 58

To clarify the phenotypes of various classes of human hematopoietic progenitor cells, we used a multicolor staining protocol in conjunction with CD34 and a newly developed mouse antihuman c-kit proto-oncogene product (KIT) monoclonal antibody (MoAb). We characterized three cell fractions in CD34+ cells that express KITlow and KIThigh cells in addition to KIT- cells. A clonogenic assay showed that most granulocyte-macrophage colony-forming cells (GM-CFC) were present in CD34+KIThigh populations, whereas erythroid burst-forming cells (BFU-E) were detected mainly in the CD34+KITlow population. CD34(+)-KIT- fraction contained a small number of BFU-E. Morphologic analysis showed that blast-like cells were more enriched in the CD34+KITlow fraction. KITlow cells contained CD34+CD38- cells that were considered to be very primitive progenitor cells, as determined by a replating assay. To clarify the biologic differences between both fractions, we examined the more primitive progenitor cell functions by assessing long-term culture-initiating cells (LTC-IC) on the stromal cells. At week 2, more CFC recovered from the culture in the fraction initiated with a CD34+KIThigh population. However, more LTC-IC were present during weeks 5 to 9 in the CD34+KITlow population. These results indicate that primitive progenitors are more enriched in the KITlow population and that the KIThigh population contains many GM-committed progenitor cells. We also showed that anti-KIT MoAb inhibited the ability of CD34+ cells to generate CFC on the stromal layer in the LTC system. This suppressive effect was more evident in the generation of BFU-E by CD34+KITlow cells. Moreover, we confirmed that CD34+KIThigh cells emerged from CD34+KITlow cells during coculture with allogeneic stromal cells or from liquid culture in the presence of stem cell factor (SCF), interleukin-6, and erythropoietin. These results emphasize the pivotal role of the KIT and SCF interaction in hematopoiesis and indicate that KITlow cells are more primitive than KIThigh cells.
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PMID:Human primitive hematopoietic progenitor cells are more enriched in KITlow cells than in KIThigh cells. 769 77

We investigated hematopoietic growth factor (HGF) and cytokine gene expression in the bone marrow (BM) and peripheral blood (PB) of healthy individuals as a starting point for delineating the physiologic role of cytokines in steady state hematopoiesis. BM biopsy specimens and PB samples from 7 healthy individuals were analyzed by polymerase chain reaction amplification of reverse-transcribed RNA using gene-specific primer sets. Consistent gene expression in the BM of all 7 individuals was detected for macrophage colony-stimulating factor (CSF), stem cell factor, interleukin-6 (IL-6), IL-7, erythroid-potentiating factor, erythroid-differentiating factor, and insulinlike growth factor 1, all cytokines with reported direct stimulatory effects on in vitro hematopoiesis. Of these, erythroid-potentiating factor and erythroid-differentiating factor appeared to be the only stimulating factors that were also expressed in the PB. Among the cytokines with inhibitory effects on in vitro hematopoiesis IL-4, tumor necrosis factor-alpha (TNF-alpha), TNF-beta, transforming growth factor-beta, and macrophage inflammatory protein-1 alpha were expressed in the BM of the 7 individuals. Except for TNF-alpha, the latter cytokines were also expressed in the PB. Consistent expression in the BM and PB of all tested individuals was also observed for IL-1 beta, IL-1 receptor antagonist, and IL-1 beta converting enzyme, which are all members of the IL-1 family with a possible indirect effect on hematopoiesis. Remarkably, no expression of granulocyte CSF, granulocyte-macrophage CSF, and IL-3 was found in the BM or PB of all investigated individuals (n = 15). This was also the case for IL-1 alpha, IL-2, IL-5, IL-9, IL-12, IL-13, leukemia-inhibiting factor, interferon-gamma, and inhibin. Weak IL-8 and IL-10 expression was found in the BM and/or PB of a minority of investigated individuals. These findings provide insight into which cytokines or HGFs potentially are involved in the autocrine or paracrine regulation of in vivo steady state hematopoiesis. The absence of expression of granulocyte CSF, granulocyte-macrophage CSF, and IL-3 in the BM of healthy individuals implicates that it is highly unlikely that these HGFs are involved in the autocrine or paracrine regulation of constitutive hematopoiesis.
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PMID:Constitutive in vivo cytokine and hematopoietic growth factor gene expression in the bone marrow and peripheral blood of healthy individuals. 771 76

Infection with cytomegalovirus (CMV) continues to be one of the most common complications following allogeneic bone marrow transplantation. The gravest danger for the host occurs when the virus is reactivated as a result of immunosuppression. In this report we studied the effects of sublethal murine cytomegalovirus (MCMV) infection on the hemopoietic system including bone marrow (BM) cellularity, production of colony stimulating factor (CSF) and interleukin-6 (IL-6) and the development of granulocyte-macrophage colony forming units (CFU-GM), and BM stromal cell viability. Our findings show that the virus infection led to a significant decrease in the number of BM cells and in the production levels of CSF and IL-6. There was also a decrease in the number of stromal cells, as reflected by the number of colony forming unit fibroblasts (CFU-F), and in the relative number of CFU-GM progenitors. Treatment of MCMV infected mice with the immunomodulator AS101 [ammonium trichloro (dioxyethylene 0-0')tellurate] restored significantly CSF and IL-6 production by BM cells to levels of uninfected control mice as well as the number of CFU-F and stromal cell elements which consequently led to the restoration of the total number of BM cells. Results presented here indicate that AS101 may have immunomodulatory effects on MCMV mediated myelosuppression. Administration of AS101 to patients with CMV associated BM damage may improve the restoration of their BM function.
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PMID:Restoration of murine cytomegalovirus (MCMV) induced myelosuppression by AS101. 772 28

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.
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PMID:Abnormal function of the bone marrow microenvironment in chronic myelogenous leukemia: role of malignant stromal macrophages. 778 Jan 47

The synthesis and release of parathyroid hormone-related protein (PTHrP) could be influenced in a paracrine or autocrine manner by substances present around or inside tumours, such as bone or stromal cell-derived cytokines, factors produced by the tumour itself or by peritumoural inflammatory cells. We investigated the effects of various cytokines known to be synthesized by osteoblasts, stromal cells, leucocytes or cancer cells, on PTHrP production by the human lung squamous cell carcinoma line BEN. The influence of tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) was studied, and compared with those of insulin-like growth factors-I and -II (IGF-I, IGF-II), or macrophage- or granulocyte-macrophage colony-stimulating factors (M-CSF, GM-CSF). TNF-alpha caused a 1.9 +/- 0.1-fold increase in immunoreactive PTHrP production, which was maximal by 24 h of incubation. IL-6 caused a 2.3 +/- 0.2-fold increase, which was maximal by 16 h. These effects, which were time- and concentration-dependent, were blocked by monoclonal antibodies raised against the corresponding cytokine. An increase of PTHrP mRNA was found in IL-6-treated cells. IGF-I and IGF-II increased PTHrP production by 2.0 +/- 0.3- and 2.3 +/- 0.1-fold respectively. Neither M-CSF nor GM-CSF altered PTHrP production up to 64 h of incubation. PTHrP production was not affected by varying extracellular calcium concentrations, but was decreased by incubation with 100 nmol/l dexamethasone.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of parathyroid hormone-related protein production in a human lung squamous cell carcinoma line. 782 96

A replication-defective recombinant retrovirus containing the human papilloma virus E6/E7 genes (LXSN-16 E6E7) was used to immortalize stromal cells from human marrow. The E6/E7 gene products interfere with the function of tumor-suppressor proteins p53 and Rb, respectively, thereby preventing cell cycle arrest without causing significant transformation. Twenty-seven immortalized clones designated HS-1 to HS-27 were isolated, four of which are characterized in this report. Two cell lines, HS-5 and HS-21, appear to be fibroblastoid and secrete significant levels of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage-CSF (GM-CSF), macrophage-CSF (M-CSF), Kit ligand (KL), macrophage-inhibitory protein-1 alpha, interleukin-6 (IL-6), IL-8, and IL-11. However, only HS-5 supports proliferation of hematopoietic progenitor cells when cocultured in serum-deprived media with no exogenous factors. Conditioned media (CM) from HS-5 promotes growth of myeloid colonies to significantly greater extent than a cocktail of recombinant factors containing 10 ng/mL of IL-1, IL-3, IL-6, G-CSF, GM-CSF, and KL and 3 U of erythropoietin (Epo). Two additional clones, HS-23 and HS-27, resemble "blanket" cells, with an epithelioid morphology, and are much larger, broader, and flatter when compared with HS-5 and HS-21. These lines secrete low levels of growth factors and do not support proliferation of isolated progenitor cells in cocultures. CM from HS-23 and HS-27 also fail to support growth of myeloid colonies. Both HS-23 and HS-27 express relatively high levels of VCAM-1, yet HS-27 is the only line that supports the formation of "cobblestone" areas by isolated CD34+38lo cells. We hypothesize that HS-5, HS-21, HS-23, and HS-27 represent functionally distinct components of the marrow microenvironment.
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PMID:Functionally distinct human marrow stromal cell lines immortalized by transduction with the human papilloma virus E6/E7 genes. 784 21

A 52-year-old Caucasian man treated with granulocyte-macrophage colonystimulating factor (GM-CSF) developed a cutaneous eruption on legs and ankles with clinical and histologic features of erythema multiforme. Laboratory studies indicated that the eruption occurred at the time of peripheral blood lymphocyte recovery and that it was coincidental with serum peaks of interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6) and tumour necrosis factor-alpha. We postulate that GM-CSF provoked erythema multiforme in a predisposed individual as a consequence of either an inappropriate cytokine secretion or of an abnormal amplification mechanism following lymphocyte recovery.
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PMID:Erythema multiforme during GM-CSF therapy. 791 20

Cells of monocytic lineage (Mo) persistently infected with human immunodeficiency virus (HIV) have been suspected to be a major reservoir for in vivo transmission of virus to susceptible target cells. Cellular events and mechanisms that upregulate viral gene expression in such cells are important issues. Because the traffic of such cells is central to biodistribution of HIV, we have explored the impact of interaction of endothelium with HIV-1-infected U1 promonocytic cells. Coculturing of U1 with human umbilical endothelial cells (HUVEC) for 24 to 72 hours in the absence of stimulation induced HIV-1 p24 biosynthesis significantly. Antibody-blocking experiments indicated that CD11/CD18 integrins play a role in upregulation of HIV expression elicited by interaction with HUVEC. Engagement of CD11b/CD18 by adherence of U1 to surfaces coated with either the cognate ligand fibrinogen or monoclonal antibody specific for CD11b/CD18 also enhanced p24 biosynthesis. Furthermore, endothelial cells were found to constitutively synthesize and secrete soluble factors that enhanced HIV-1 synthesis. The enhancing factors, of estimated size 10 to 45 kD, were induced in HUVEC to high levels by monokines or by lipopolysaccharide, resulting in markedly enhanced HIV-1 expression by U1. These endothelial cell-derived HIV-1-enhancing factors consist of, among others, interleukin-6 (IL-6), IL-1 beta, and granulocyte-macrophage CSF (GM-CSF). Our results suggest that activation of HIV biosynthesis in infected Mo via interaction with endothelium may impact significantly on the tissue distribution and pathogenesis of HIV infections.
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PMID:Upregulation of human immunodeficiency virus-1 in chronically infected monocytic cell line by both contact with endothelial cells and cytokines. 791 48

Lymphohematopoiesis occurs in the densely packed environment of the intramedullary spaces. Primitive lymphohematopoietic stem cells exist in close apposition to a variety of supportive cells including both hemopoietic and nonhemopoietic lineages. Using an in vitro long-term Dexter liquid culture system, we have established that a variety of cytokines are produced constitutively by such stromal cells in culture. These cytokines include Steel factor, interleukin-6 (IL-6), and colony-stimulating factor (CSF-1). Granulocyte-CSF and granulocyte-macrophage-CSF mRNA can be detected after refeeding of cultures, although in quiescent cultures message for these factors is difficult to detect. Interleukin-3, IL-4, and IL-5 are not detectable by standard Northern blot analysis or bioassay of condition media. However, IL-3--detectable by reverse-transcriptase PCR and biologic activity--was confirmed by growth of factor-dependent cells on stromal cells with IL-3 antibody blocking of such growth. Stem cells resident on such stromal cells are mirrored by the high proliferative potential colony-forming cell assay and are responsive to a relatively large number of cytokines, with Steel factor being of central importance, appearing to be a critical component of various synergistic combinations. Steel factor allows reduced levels of other factors in such combinations and works early in a temporal sequence. Hematopoietic stem cells can engraft in normal nonmyeloablated hosts. Using a male/female BALB/c transplantation model, we have shown high rates of engraftment into normal animals, out after marrow infusion to 25 months, after marrow infusion and that post-5-fluorouracil bone marrow is quite deficient in such engraftment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vitro and in vivo studies of stromal niches. 799 65


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