Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin 12 (IL-12) has a key role during the initial phase of the immune response, favouring development of T helper class 1 (Th1) cells. IL-12 is composed of two subunits, p35 and p40, which are both needed for bioactivity. The level of p35 expression determines the level of bioactive IL-12 (p70), while the p40 subunit is produced in excess. In the present study we examined the sensitivity of bioactive IL-12 production by human monocytes to a corticosteroid, budesonide. We also compared the corticosteroid sensitivity of IL-12 and two other cytokines, interleukin 1beta and granulocyte-macrophage colony-stimulating factor (GM-CSF). Monocytes obtained from peripheral blood of healthy donors (n=12) were stimulated with lipopolysaccharide (LPS; 10 microg/ml; 20 h) in the presence or absence of budesonide (10(-11)-10(-7) M). The supernatants were assayed for IL-12 (p70), IL-1beta and GM-CSF concentrations using specific immunoassays. Budesonide potently inhibited the production of bioactive IL-12. A significant suppression was obtained by treatment with even very low budesonide concentrations; even 10(-11) M budesonide significantly inhibited IL-12 to 81.6+/-7.6% of the control level (P<0.05). The maximal inhibitory effect of budesonide was seen at 10(-8) M. The inhibition of IL-12 production was significantly higher than the inhibition of GM-CSF (P<0.01) or IL-1beta (P<0.001). Whereas IL-12 production was totally inhibited, GM-CSF production was inhibited to 16.4+/-3.7 and IL-1beta production to 43.1+/-7.3% of control, respectively. The dramatic capacity of corticosteroids to modulate production of IL-12 as well as other cytokines may be a major mechanism underlying the effectiveness of these drugs in a broad spectrum of inflammatory diseases.
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PMID:Effects of a corticosteroid, budesonide, on production of bioactive IL-12 by human monocytes. 981 32

Intact mycobacteria and mycobacterial cell wall extracts have been shown to inhibit the growth of human and murine bladder cancer. Their mechanism of action is, however, poorly understood. Mycobacterium phlei mycobacterial cell complex (MCC) is a cell wall preparation that has mycobacterial DNA in the form of short oligonucleotides complexed on the cell wall surface. In this study, we have investigated the possibility that MCC has anti-cancer activity that is mediated by two different mechanisms--a direct effect on cancer cell proliferation and viability and an indirect effect mediated by the production of interleukin 12 (IL-12), a cytokine known to possess anti-cancer activity. We have found that, although MCC is a potent inducer of IL-12 and IL-6 synthesis in monocytes and macrophages either in vitro or in vivo, it is unable to induce the synthesis of either IL-12, IL-6 or granulocyte-macrophage colony-stimulating factor (GM-CSF) by the human transitional bladder cancer cell lines HT-1197 and HT-1376. MCC is not directly cytotoxic towards these cancer cells, but induces apoptosis as determined by nuclear DNA fragmentation and by the release of nuclear mitotic apparatus protein. Mycobacterium phlei DNA associated with MCC is responsible for the induction of apoptosis. Our results indicate that MCC directly effects bladder cancer cells by inhibiting cellular proliferation through the induction of apoptosis, and has the potential for an indirect anti-cancer activity by stimulating cancer-infiltrating monocytes/macrophages to synthesize IL-12.
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PMID:Mycobacterium phlei cell wall complex directly induces apoptosis in human bladder cancer cells. 988 62

Intramuscular injection of plasmid DNA encoding both subunits of the cytokine interleukin 12 (IL-12) exhibits strong antimetastatic activity against lung metastases induced by the malignant melanoma cell line B16-F10. The protective effect of IL-12 DNA is long-lasting, since administration of tumor cells 9 days after IL-12 DNA treatment prevented metastasis formation. No effects were observed with empty plasmid controls, DNA encoding the melanoma-associated antigen pmel17/gp100, the granulocyte-macrophage colony-stimulating factor GM-CSF, B7.1, or CpG-containing oligodeoxynucleotides. IL-12 DNA is required during early phases of metastasis formation and is ineffective when administered later. Its efficiency is dose dependent. The cytotoxic T cell response contributes to the antimetastatic effect as evidenced by genetically modified CD8- or perforin knockout mice. Depletion of natural killer (NK) cells by antibodies completely abrogated the effect. In contrast, the IL-12-induced antimetastatic effect was not mediated by interferon gamma (IFN-gamma) or tumor necrosis factor alpha (TNF-alpha) as shown with IFN-gamma receptor and TNF-alpha knockout mice, respectively. Toxic side effects by IL-12 were low. Our results suggest that plasmid DNA encoding IL-12 might have potential value as gene medicine against the initiation of metastasis formation.
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PMID:Long-lasting anti-metastatic efficiency of interleukin 12-encoding plasmid DNA. 1004 93

Human cord blood CD34(+)stem cells were allowed to differentiate in the presence of cytokines stem cell factor (SCF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumour necrosis factor alpha (TNF-alpha) into functional CD1a+dendritic cells (DC). A maximum of 1.9 x 10(6) CD1a+ cells were separated from the cells generated from 1.2 x 10(6) CD34(+) stem cells from an individual donor. The percentage of CD1a+cells separated rose to a maximum of 27% at day 11 and fell to 8% at 21 days. Reverse transcription-polymerase chain reaction analysis showed that interleukin 2 receptor, interleukin 3 receptor, interleukin 6 receptor, interleukin 12 receptor (IL-12R) and signal transducer and activator of transcription (STAT) 3, STAT 4 mRNA was expressed in all CD1a+cell populations throughout and appears to be constitutive. Expression of IL-12RmRNA was unexpected in CD1a+DC normally considered to be of myeloid lineage. Expression of interleukin 12 (IL-12) p40 subunit mRNA was not detected. Intermittent expression of the IL-12p35 subunit and IL-4R mRNA suggested that gene expression is inducible, but not obviously correlated with progressive DC development. Expression of mRNA for a spectrum of cytokine receptors indicates that CD1a+DC have the potential to respond to a variety of maturational signals.
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PMID:Gene expression during differentiation of human dendritic cells from cord blood cd34 stem cells. 1008 31

An obstacle to developing a vaccine against human respiratory syncytial virus (RSV) is that natural infection typically does not confer solid immunity to reinfection. To investigate methods to augment the immune response, recombinant RSV (rRSV) was constructed that expresses murine granulocyte-macrophage colony-stimulating factor (mGM-CSF) from a transcription cassette inserted into the G-F intergenic region. Replication of rRSV/mGM-CSF in the upper and lower respiratory tracts of BALB/c mice was reduced 23- to 74- and 5- to 588-fold, respectively, compared to that of the parental rRSV. Despite this strong attenuation of replication, the level of RSV-specific serum antibodies induced by rRSV/mGM-CSF was comparable to, or marginally higher than, that of the parental rRSV. The induction of RSV-specific CD8(+) cytotoxic T cells was moderately reduced during the initial infection, which might be a consequence of reduced antigen expression. Mice infected with rRSV/mGM-CSF had elevated levels of pulmonary mRNA for gamma interferon (IFN-gamma) and interleukin 12 (IL-12) p40 compared to animals infected by wild-type rRSV. Elevated synthesis of IFN-gamma could account for the restriction of RSV replication, as was observed previously with an IFN-gamma-expressing rRSV. The accumulation of total pulmonary mononuclear cells and total CD4(+) T lymphocytes was accelerated in animals infected with rRSV/mGM-CSF compared to that in animals infected with the control virus, and the level of IFN-gamma-positive or IL-4-positive pulmonary CD4(+) cells was elevated approximately twofold. The number of pulmonary lymphoid and myeloid dendritic cells and macrophages was increased up to fourfold in mice infected with rRSV/mGM-CSF compared to those infected with the parental rRSV, and the mean expression of major histocompatibility complex class II molecules, a marker of activation, was significantly increased in the two subsets of dendritic cells. Enhanced antigen presentation likely accounts for the maintenance of a strong antibody response despite reduced viral replication and would be a desirable property for a live attenuated rRSV vaccine.
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PMID:Granulocyte-macrophage colony-stimulating factor expressed by recombinant respiratory syncytial virus attenuates viral replication and increases the level of pulmonary antigen-presenting cells. 1171 4

We studied the effects of administration of several cytokines, including progenipoietin-1 (ProGP-1), Flt-3 ligand (FL), granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor in a pegylated form (pGM-CSF), on dendritic cell (DC) populations in mouse spleen. ProGP-1 produced the most striking increase in overall DC numbers, apparently more than its constituent FL and G-CSF components. However, the expansion in DC numbers was strongly subpopulation selective, with ProGP-1 and FL producing selective expansion of CD8+ DCs, whereas pGM-CSF produced selective expansion of CD8- DCs. Surprising differences were observed between the effects of murine and human recombinant FL preparations on murine DCs. Many of the biologic functions of the DC subpopulations expanded by cytokines remained intact, including the capacity of the ProGP-1- and FL-expanded CD8+ DCs to produce the T-helper-1-biasing cytokine interleukin 12 (IL-12). However, the expanded DCs from all but G-CSF-treated mice were deficient in the ability to make interferon gamma, and the CD8+ DCs produced with pGM-CSF treatment had an abrogated capacity to form bioactive IL-12. Such selective expansion of DC populations and alterations in their cytokine-secretion capacity have implications for clinical use of the studied cytokines in immune modulation.
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PMID:Effects of administration of progenipoietin 1, Flt-3 ligand, granulocyte colony-stimulating factor, and pegylated granulocyte-macrophage colony-stimulating factor on dendritic cell subsets in mice. 1187 88

Increasing evidence indicates that the capacity to induce protective Th1 immune responses is impaired in early childhood, an observation that can be partially attributed to deficiencies in antigen-presenting-cell function. Synthesis of interleukin 12 (IL-12), a key Th1-trophic cytokine, is markedly reduced in the neonatal period, though there is a paucity of knowledge concerning the ontogeny of IL-12-synthetic capacity throughout the childhood years. Hence, we examined the production of bioactive IL-12 p70 by circulating mononuclear cells in a population of healthy individuals. As expected, the capacity to synthesize IL-12 p70 in response to either lipopolysaccharide or heat-killed Staphylococcus aureus was markedly impaired at birth, even after priming of cells with gamma interferon. Surprisingly however, IL-12 p70 synthesis by peripheral blood mononuclear cells from both 5- and 12-year-old children was still substantially below that seen in adults, and this did not appear to be related to excessive production of IL-10. In contrast, dendritic cells from adults and neonates, derived from monocytes with granulocyte-macrophage colony-stimulating factor and IL-4, synthesized equivalent amounts of IL-12 p70 in response to microbial stimulation. This indicates that the impaired capacity for IL-12 synthesis in childhood is not an intrinsic property of circulating mononuclear cells but rather can be readily overcome in response to appropriate maturational stimuli. Because IL-12 arose predominantly from circulating HLA-DR(+) cells that lacked B-cell- and monocyte-specific markers, we propose that the slow maturation of IL-12-synthetic capacity in the childhood years can be attributed to deficiencies in the number and/or function of dendritic cells.
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PMID:Development of interleukin-12-producing capacity throughout childhood. 1243 28

Tumor cells, injected s.c., were maintained until spontaneous metastases to the lungs were established in all of the mice. Mice were then treated with a single dose of cytokine-encapsulated biodegradable microspheres injected directly into primary s.c. tumors to achieve a local and sustained release of interleukin 12 (IL-12), granulocyte-macrophage colony-stimulating factor (GM-CSF), or a combination of these cytokines to the tumor microenvironment. The s.c. tumors were surgically excised 6 days after microsphere injections, and the mice were monitored for recurrence of the primary tumor, survival, and progression of metastatic disease. Combined neoadjuvant treatment with IL-12 and GM-CSF microspheres was superior to all other treatments in reducing the recurrence of primary tumors, enhancing postoperative survival, and suppressing established metastatic disease. Long-term survival analysis demonstrated that intratumoral injection of IL-12 + GM-CSF-loaded microspheres resulted in the complete cure of disseminated disease in the majority of the animals. The addition of systemic low-dose IL-2 therapy to the treatment protocol resulted in the loss of the antitumor activity induced by IL-12 + GM-CSF treatment. In vivo lymphocyte subset depletions established that both T- and natural killer-cell subsets were required for the suppression of primary and metastatic tumors. Long-term, tumor-specific T-cell activity was demonstrated by immunohistochemical analysis of metastatic lesions, IFN-gamma enzyme-linked immunosorbent spot (ELISPOT) assays and tumor challenge studies. These results establish that neoadjuvant in situ tumor immunotherapy with IL-12 + GM-CSF microspheres induces both innate and adaptive antitumor immune responses resulting in the eradication of disseminated disease.
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PMID:Cancer immunotherapy with interleukin 12 and granulocyte-macrophage colony-stimulating factor-encapsulated microspheres: coinduction of innate and adaptive antitumor immunity and cure of disseminated disease. 1249 67

Myeloma cells express the idiotype (Id)-specific antigen that may be targeted by Id vaccination. Six patients with stage I IgG myeloma were immunized with the autologous purified M component together with the adjuvant cytokines interleukin 12 (IL-12) alone or in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF). The effect of Id vaccination on circulating clonal tumor B cells was monitored by a real-time allele-specific oligonucleotide polymerase chain reaction method. No other treatment was given. Reduction of blood tumor mass was observed in 4 of 6 patients, with one patient achieving a complete molecular remission in blood. In 3 of these 4 patients an Id-specific T-cell response was induced. In the remaining 2 patients with an unchanged level of blood tumor cells, one patient mounted a T-cell response, whereas the other did not. No significant change in the serum M protein level was noted. Id vaccination may target clonal B cells, suggesting that this strategy might be conducive to achieving tumor control. The clinical significance of these findings remains to be established.
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PMID:Idiotype vaccination in multiple myeloma induced a reduction of circulating clonal tumor B cells. 1257 27

The chimeric monoclonal antibody to tumor necrosis factor (TNF), infliximab, is an effective therapy for Crohn's disease. However, the formation of human anti-chimeric antibodies to infliximab (immunogenicity) can lead to loss of efficacy as well as acute infusion reactions and delayed hypersensitivity reactions. The fully human monoclonal antibody adalimumab and the pegylated humanized monoclonal antibody fragment CDP870 are biologic therapies against TNF that might be effective for Crohn's disease and less immunogenic than infliximab. Other potential alternatives to infliximab for Crohn's disease include the humanized anti-adhesion molecule antibodies natalizumab and MLN-02, the humanized anti-interleukin 12 antibody ABT-874, the humanized anti-interferon g antibody fontolizumab, the humanized anti-interleukin 6 receptor antibody MRA, and human recombinant granulocyte macrophage colony stimulating factor (sargramostim). Some, or all, of these therapies will likely represent important treatments for Crohn's disease in the future.
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PMID:How future tumor necrosis factor antagonists and other compounds will meet the remaining challenges in Crohn's disease. 1558 28


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