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)

The ifosfamide/carboplatin/etoposide (ICE) combination represents an active chemotherapy regimen across a wide variety of disease types. The most common limiting toxicity for all three of these agents individually and in combination is myelosuppression. Thus, this regimen represents an ideal model to evaluate the role of hematopoietic growth factor support in amelioration of hematologic toxicity, maintenance of dose intensity, and dose escalation. While chemotherapy strategies using colony-stimulating factors have abrogated neutropenia, cumulative thrombocytopenia is common with many chemotherapy regimens, including ICE chemotherapy. In preclinical and phase II trials, monotherapy with recombinant human interleukin-6 (IL-6) has demonstrated substantial thrombopoietic activity, but with little enhancement of neutrophil recovery. Thus, this study was designed to evaluate combination cytokine therapy with both recombinant IL-6 and granulocyte colony-stimulating factor (G-CSF) after ICE chemotherapy. Previously untreated patients with inoperable non-small cell lung cancer are eligible. Treatment includes two monthly cycles of ifosfamide 2,000 mg/m2 with mesna 1,600 mg/m2 intravenously on days 1, 2, and 3, carboplatin 350 mg/m2 intravenously on day 1 only, and etoposide 75 mg/m2 intravenously on days 1, 2, and 3. All patients then receive G-CSF at a dose of 5 micrograms/kg/d subcutaneously beginning on day 4 until a postnadir absolute neutrophil count of more than 10 x 10(9)/L. Cohorts of patients (n = 15) are randomized to receive 0, 1, 2.5, or 5 micrograms/kg/d of IL-6 subcutaneously on days 4 to 13 in successive cohorts. This study has now reached its target accrual in all cohorts. The final data analysis is in progress. It is hoped that this trial will define the safety and tolerability of the simultaneous administration of IL-6 and G-CSF following ICE chemotherapy in patients with non-small cell lung cancer. In addition, this trial should determine the biologic activity and hematopoietic recovery observed during the simultaneous administration of these two cytokines in this setting.
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PMID:The role of hematopoietic growth factors in support of ifosfamide/carboplatin/etoposide chemotherapy. 754 16

In the osteopetrotic op/op mouse, the absence of macrophage colony-stimulating factor (M-CSF) prevents the growth of macrophages and osteoclasts and, consequently, bone resorption. In the present study, we investigated whether this deficiency in M-CSF production alters the production of cytokines in op/op bones. Calvariae of phenotypically normal (+/?) and op/op mice were stimulated in vitro with lipopolysaccharide or Pasteurella multocida toxin to produce cytokines. Interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) synthesis was the same both in calvaria from osteopetrotic and phenotypically normal animals. However, the production of granulocyte colony-stimulating factor (G-CSF), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF alpha) was lower in calvaria from op/op animals than was the case in +/? calvaria. Thus, the lack of biologically active M-CSF causes defects which are not compensated by cells independent of M-CSF.
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PMID:Cytokine production by calvariae of osteopetrotic mice. 757 58

Tumors obtained from v-Ha-ras-transformed PB-3c cells are characterized by autocrine interleukin-3 (IL3) expression, which occurs either without (class I tumors) or with enhanced transcription (class II tumors). To address possible post-transcriptional mechanisms of IL3 expression, IL3 mRNA stability was examined in both tumor classes. Increased stability of IL3 mRNA was detected in class I tumor lines (t1/2 > 3 h), whereas rapid decay of IL3 transcripts (t1/2 < 0.5 h) was found in class II tumor lines. In both tumor classes, the c-myc and interleukin-6 transcripts were short-lived. Transcripts of a constitutively expressed IL3 reporter gene were stable in class I tumor cells but unstable in class II tumor cells, suggesting that IL3 mRNA stabilization involved a trans-acting mechanism. Rapid decay of IL3 reporter transcripts was observed in untransformed PB-3c as well as in v-Ha-ras expressing precursor cells linking transcript stabilization to the tumor stage. Reporter transcript stabilization in class I tumor cells correlated with increased IL3 production. Deletion of the AU-rich element from the IL3 reporter gene further augmented IL3 mRNA levels as well as IL3 production, suggesting that the stabilizing mechanism in class I tumor cells is not equivalent to AU-rich element deletion.
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PMID:Interleukin-3 mRNA stabilization by a trans-acting mechanism in autocrine tumors lacking interleukin-3 gene rearrangements. 765 42

Present methods for long-term hematopoietic culture (LTHC) employ a static culture environment which is not well-characterized. Primitive long-term culture-initiating cell (LTC-IC) numbers have been shown to decline in conventional static human LTHC, even with exogenous cytokine combinations. We have expanded human hematopoietic cells from umbilical cord blood on a preformed marrow stroma with synergistic cytokine combinations in a novel perfusion bioreactor system, which continuously maintained culture conditions within desired ranges. Interleukin-3 (IL-3) and interleukin-6 (IL-6) in perfusion culture resulted in rapid 7-day expansion of granulocyte-macrophage colony forming units (CFU-GM, 11-fold), erythroid burst-forming units (BFU-E, 2.5-fold), and granulocyte-erythroid-macrophage colony forming units (CFU-Mix, 2.4-fold), compared to 6-fold, 1.4-fold, and no expansion, respectively, in static cultures. Addition of stem cell factor (SCF) to IL-3/IL-6 in static culture increased the extent of CFU-GM expansion (to 9-fold), but did not result in BFU-E or CFU-Mix expansion. In perfusion cultures with IL-3/IL-6/SCF, much greater expansions of CFU-GM (18-fold) and CFU-Mix (5.3-fold) were obtained. More importantly, expansion of LTC-IC (nearly 3-fold in two of three experiments) was only obtained with IL-3/IL-6/SCF and perfusion. The ability to expand hematopoietic cells while maintaining or expanding primitive progenitors has potential clinical applications in bone marrow transplantation and gene therapy.
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PMID:Expansion of primitive human hematopoietic progenitors in a perfusion bioreactor system with IL-3, IL-6, and stem cell factor. 768 Feb 9

Oncostatin M (OM) is structurally and functionally related to a subclass of hematopoietic cytokines including leukemia-inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), granulocyte colony-stimulating factor (G-CSF), and interleukin-6 (IL-6). Using human endothelial cells (HEC) as a model for cytokine regulation of hematopoietic growth factor expression, we tested OM as an inducer of colony-stimulating activity. Colony-forming cell assays supplemented with culture supernatants from OM-treated HEC contained a threefold increase in colony-forming unit granulocyte-macrophage colonies. Specific immunoassay (enzyme-linked immunosorbent assay) of culture supernatants indicated that OM treatment of HEC resulted in a dose- and time-dependent increase in the accumulation of G-CSF and granulocyte-macrophage CSF (GM-CSF) (> 28-fold). The ED50 for OM induction of G-CSF and GM-CSF protein expression was 17 and 7 pmol/L, respectively. Increased protein expression was associated with a similar increase in steady-state expression of G-CSF and GM-CSF mRNA. Furthermore, a period of 12 to 24 hours elapsed before there were measurable increases in CSF expression, suggesting that OM may stimulate CSF production through a mechanism requiring the synthesis or activation of a secondary mediating factor or pathway. These findings provide the first evidence that OM may regulate myelopoiesis by inducing the cellular expression of hematopoietic growth factors.
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PMID:Regulation of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor expression by oncostatin M. 768 88

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

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

We have extracted and purified Yersinia enterocolitica ATCC 9610 porins that have molecular weights of 36-38 kDa. They inhibited phagocytosis and phagosome-lysosome fusion (30%) in human monocytes and caused enhanced nitrite production. Preincubation of polymorphonuclear neutrophils with porins (1-10 micrograms/ml/10(6) cells) induced a reduction in chemotaxis, adherence to nylon wool and chemiluminescence. Human lymphomonocytes treated with Y. enterocolitica porins showed a distinctive cytokine profile. Interleukin-1 alpha, interleukin-6 and tumour necrosis factor alpha were released within 3-6 h, while interleukin-8, gamma interferon and granulocyte-macrophage colony stimulating factor were released after 18 h. Interleukin-3 and interleukin-4 were not detected at up to 48 h of incubation. In conclusion, these immunomodulating and histotropic properties may account for Y. enterocolitica infection and its sequelae.
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PMID:Properties of Yersinia enterocolitica porins: interference with biological functions of phagocytes, nitric oxide production and selective cytokine release. 799 43

Cellular turnover of the hematopoietic system is supported by a small population of cells termed hematopoietic stem cells. Stem cells are capable of self-renewal and differentiation into individual lymphomyeloid lineages. Available evidence indicates that the decision of a stem cell to self-renew or differentiate and the decision of a multipotential progenitor to select a lineage pathway during differentiation (commitment) are intrinsic to the progenitors and are stochastic in nature. In contrast, proliferative kinetics of the progenitors, namely, survival and expansion of the progenitors, appear to be controlled by a number of interacting cytokines. Whereas proliferation and maturation of committed progenitors are controlled by late-acting factors such as erythropoietin, macrophage colony-stimulating factor, granulocyte colony-stimulating factor, and interleukin-5, progenitors at earlier stages of development are controlled by a group of several overlapping cytokines. Interleukin-3, granulocyte/macrophage colony-stimulating factor, and interleukin-4 regulate proliferation of multipotential progenitors only after they are triggered to exit from dormancy state. Triggering of cycling of dormant primitive progenitors and proliferation of lymphohemopoietic primitive progenitors appear to require interactions of early acting cytokines including interleukin-6, granulocyte colony-stimulating factor, interleukin-11, interleukin-12, leukemia inhibitory factor, and steel factor.
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PMID:Hematopoiesis. 808 74

Mammalian hemopoiesis results from a complex interaction between hemopoietic progenitor cells, stromal cells and extracellular matrix components, orchestrated by specific glycoprotein growth factors. Recently, these growth factors have been shown to possess an important function, apart from stimulation of proliferation, and that is suppression of an active cellular process of programmed cell death, or apoptosis. Highly specific biochemical and morphologic changes have been shown to occur during apoptosis, but their reflections on cellular functions are poorly understood. Interleukin-3 (IL-3)-dependent FDCP-1 (factor-dependent cell lines cloned in Paterson Laboratories) cells were studied for their ability to adhere to hemopoietic stroma in a temporal fashion under conditions of apoptosis and following rescue from apoptosis with growth factor. It was found that cloned FDCP-1 cells always maintained, in the presence of a source of IL-3 (either WEHI conditioned medium or rm-IL-3), bound cloned hemopoietic stromal cell GB1/6 in a constant fashion for 20 hours, while cells starved of IL-3 experienced a 50% time-dependent decrement in binding. If IL-3 were added back to FDCP-1 that had been starved of growth factor for 8 hours, but not 12 hours, adherence to stroma was restored to that of control cells always in the presence of IL-3. Granulocyte/macrophage colony-stimulating factor (GM-CSF), Interleukin-6 (IL-6) and transforming growth factor-beta (TGF-beta) did not restore cytoadherence. By transmission electron microscopy, nucleus and cytoplasm of IL-3-replenished cells resembled that of control cells. These data indicate that at least some events related to apoptosis were reversible for a period up to 8 hours, but not 12 hours, in cells that had been rescued by readdition of IL-3. These findings offer important insight into a way in which bone marrow progenitor cells may be maintained in a condition that optimizes their ability to engraft stroma during transplantation.
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PMID:Restorative effect of IL-3 on adherence of cloned hemopoietic progenitor cell to stromal cell. 841 60


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