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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytokine secretion by endometrial cells from estrous and mated mice was measured using specific bioassays. The granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-6 (IL-6) contents of uterine intraluminal fluid were elevated greater than 20-fold and 250-fold respectively following mating, and both cytokines were synthesized in abundance in vitro by uterine cells harvested at estrus and on Day 1 of pregnancy. Synthesis was not impaired in genetically lymphocyte-deficient nude, SCID, or beige mice. To determine the cellular origin of the cytokines, a panning technique employing monoclonal antibodies against a range of leukocyte and other lineage markers was used to isolate uterine cell subsets in vitro. These experiments identified glandular and/or luminal epithelial cells as the major source of GM-CSF and IL-6 in estrous and pregnant uteri. Stromal fibroblasts also synthesized IL-6, as did macrophages in mated mice. Epithelial cells harvested from midgestation uteri secreted GM-CSF and IL-6 in quantities similar to those of cells from estrous and mated mice. Bioactivities of both cytokines derived from epithelial cells were neutralized by specific antibodies, and size-exclusion chromatography of conditioned media from uterine cells revealed peaks of GM-CSF and IL-6 bioactivity with M(r) 23,000 and 23,000-26,000, respectively. Bioassay of luminal fluids and culture supernatants were negative for the cytokines interleukin-1, interleukin-2, interleukin-3, and tumor necrosis factor-alpha. These studies identify murine uterine epithelium as a potent source of the cytokines GM-CSF and IL-6, which we postulate have potentially important functions in pregnancy through actions on target cells in both the uterus and the conceptus.
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PMID:Uterine epithelial cells synthesize granulocyte-macrophage colony-stimulating factor and interleukin-6 in pregnant and nonpregnant mice. 139 4

The SCID (severe combined immunodeficient) mouse lacks both B and T cells and tolerates injected mononuclear cells from humans, the principal hosts of Mycobacterium leprae. A SCID mouse model of leprosy could be useful to investigate potential vaccine strategies using human cells in a context in which the growth of the organism is monitored. Initial experiments determined that SCID mice are more susceptible than normal mice to infection and dissemination of M. leprae. Cells from humans, either BCG vaccinated or from countries where leprosy is endemic, were stimulated in vitro with a number of mycobacterial antigens--whole M. leprae, M. leprae cell walls, purified protein derivative of M. tuberculosis, and Mycobacterium bovis BCG--and tested for proliferation and production of interleukin-6, tumor necrosis factor alpha, and gamma interferon. Cell walls were the most efficient and consistent in inducing all of these activities. In vitro-activated human cells retain function better after injection into SCID mice than nonactivated cells. To test the ability of cells to affect the growth of M. leprae in the footpads of SCID mice, cells from a known responder to mycobacterial antigens and from a nonresponder were activated by M. leprae cell wall antigens. The cells were harvested and coinjected with fresh M. leprae into the right hind footpads of SCID mice. After 3 months, there was no growth of M. leprae in the footpads of mice coinjected with cells from the mycobacterial antigen responder, while growth was uninhibited in mice receiving cells from the nonresponder. Future experiments will determine requirements for antigen specificity in inhibiting M. leprae multiplication.
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PMID:Infection of SCID mice with Mycobacterium leprae and control with antigen-activated "immune" human peripheral blood mononuclear cells. 786 26

Avipoxviruses have recently been studied as potential vectors for the delivery of heterologous vaccine antigen. Because these viruses abortively infect mammalian cells yet still effectively present encoded foreign genes to the host immune system, they offer a safer but effective alternative to other live virus vectors. We have examined the effect of coexpressing the cytokine interleukin-6 or gamma interferon on immune responses to a recombinant fowlpox virus expressing influenza virus hemagglutinin. The encoded cytokine was expressed for prolonged periods in infected cell culture with little cytopathic effect due to the abortive nature of the infection. In mice, vector-expressed cytokine dramatically altered immune responses induced by the coexpressed hemagglutinin antigen. Expression of interleukin-6 augmented both primary systemic and mucosal antibody responses and primed for enhanced recall responses. In contrast, expression of gamma interferon markedly inhibited antibody responses without affecting the generation of cell-mediated immunity. The safety of these constructs was demonstrated in mice with severe combined immunodeficiency, and no side effects due to cytokine expression were observed. In summary, fowlpox virus vectors encoding cytokines represent a safe and effective vaccine strategy which may be used to selectively manipulate the immune response.
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PMID:Selective induction of immune responses by cytokines coexpressed in recombinant fowlpox virus. 796 3

The production of interleukin-6 (IL-6) and its possible relationship to host resistance and inflammatory response to Pneumocystis carinii infection were examined in mice with severe combined immunodeficiency (SCID mice). IL-6 activity was detected in the serum and lungs of P. carinii-infected mice but not in mice free of P. carinii. Moreover, the IL-6 levels in P. carinii-infected mice increased markedly after spleen cell reconstitution but then decreased to an undetectable level after the clearance of P. carinii. However, neutralization of IL-6 activity in spleen cell-reconstituted SCID mice by treatment with anti-IL-6 immunoglobulin G (IgG) resulted in no significant effect on the clearance of P. carinii (P > 0.05). Both the serum and lungs of treated mice contained an excess amount of anti-IL-6 IgG and lacked detectable IL-6. These results suggest that failure to inhibit the P. carinii clearance by anti-IL-6 treatment was not due to insufficient administration of antibody or incomplete neutralization of IL-6 activity. However, compared with mice receiving rat control IgG, mice treated with anti-IL-6 IgG had significantly higher numbers of neutrophils and lymphocytes (particularly CD8+ cells) in the lung lavage fluids (P < 0.05 for both) at day 19 after reconstitution. In addition, the levels of both total IgG (P < 0.001) and P. carinii-specific antibodies (P < 0.05) in the serum of mice treated with anti-IL-6 were significantly higher than those in control mice. These results indicate that although P. carinii infection causes both local and systemic production of IL-6 in SCID mice, IL-6 does not appear to play a crucial role in the clearance of P. carinii. However, it appears that during resolution of P. carinii pneumonia, IL-6 plays a role in the regulation of pulmonary inflammation and antibody responses.
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PMID:Interleukin-6 production in a murine model of Pneumocystis carinii pneumonia: relation to resistance and inflammatory response. 841 70

In order to investigate activation of the innate immune system in murine toxoplasmosis, T- and B-cell-deficient SCID mice and their co-isogenic immunocompetent C.B-17 counterparts were orally infected with a low-virulent strain of Toxoplasma gondii (DX strain). SCID mice developed a fatal necrotizing toxoplasmosis, whereas CD4+ and CD8+ T cells contributing to inflammatory infiltrates conferred resistance to immunocompetent mice. Significant amounts of interferon-gamma (IFN-gamma) were detectable in SCID mice. The most likely source for this cytokine is activated natural killer (NK) cells. In comparison to immunocompetent mice IFN-gamma levels were reduced in cerebrospinal fluid (CSF) and serum of SCID mice at days 7 and 14 of disease. Similar amounts of tumour necrosis factor (TNF) were detected in both strains of mice. In addition, immunohistochemistry showed major histocompatibility complex (MHC) class II antigen expression on SCID and C.B-17 microglial cells and macrophages demonstrating activation of these cells in both strains. However, the up-regulation of MHC class II antigen on microglia was less pronounced in SCID mice, presumably due to reduced levels of IFN-gamma. Interleukin-6 (IL-6) levels in CSF and serum were elevated in both strains and correlated with systemic and intracerebral disease activity. In conclusion, our results demonstrate activation of macrophages and NK cells as the predominant defence mechanisms of the comprised SCID immune system during toxoplasma infection. This implies a major role for the innate immune system during early stages of toxoplasmosis although T cells are necessary to control the infection efficiently.
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PMID:Expression of major histocompatibility complex class II antigens and levels of interferon-gamma, tumour necrosis factor, and interleukin-6 in cerebrospinal fluid and serum in Toxoplasma gondii-infected SCID and immunocompetent C.B-17 mice. 847 25

The cellular source of interleukin-6 (IL-6) during infection of mice with Listeria monocytogenes was investigated both in vitro and in vivo. Peritoneal cells taken at intervals from infected mice and cultured in vitro without added stimulus produced high titers of IL-6 peaking 2 days postinfection in a time course similar to that observed in vivo. Adherent cells with the morphology of macrophages were a major source of this IL-6. Spleen cells similarly harvested at intervals and cultured with heat-killed Listeria or heat-killed Brucella organisms as specific and nonspecific stimuli, respectively, showed two distinct IL-6 responses: (i) an early-phase response up to 5 days after infection when IL-6 production was elicited by either a specific or nonspecific stimulus, and when depletion of T cells had no effect, and (ii) a later response 7 to 10 days after infection when very high levels of IL-6 were produced in response to a specific stimulus. This response was lost when T cells were depleted in vitro or in vivo or in spleen cell cultures from mice with severe combined immunodeficiency. However, studies in vivo failed to show an important role for T cells governing serum IL-6. We conclude that most of IL-6 detected in vivo is produced by nonlymphocytes. Whether IL-6 produced by T lymphocytes in local foci of infection has any role in resolution of that infection is unknown.
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PMID:The cellular source of interleukin-6 during Listeria infection. 850 Sep

Osteolytic bone destruction and its complications, bone pain, pathologic fractures, and hypercalcemia, are a major source of morbidity and mortality in patients with multiple myeloma. The bone destruction in multiple myeloma is due to increased osteoclast (OCL) activity and decreased bone formation in areas of bone adjacent to myeloma cells. The mechanisms underlying osteolysis in multiple myeloma in vivo are unclear. We used a human plasma cell leukemia cell line, ARH-77, that has disseminated growth in mice with severe combined immunodeficiency (SCID) and expresses IgG kappa, as a model for human multiple myeloma, SCID mice were irradiated with 400 rads and mice were injected either with 10(6) ARH-77 cells intravenously (ARH-77 mice) or vehicle 24 hours after irradiation. Development of bone disease was assessed by blood ionized calcium levels, x-rays, and histology. All ARH-77, but none of control mice that survived irradiation, developed hind limb paralysis 28 to 35 days after injection and developed hypercalcemia (1.35 to 1.46 mmol/L) a mean of 5 days after becoming paraplegic. Lytic bone lesions were detected using x-rays in all the hypercalcemic mice examined. No lytic lesions or hypercalcemia developed in the controls. Controls or ARH-77 mice, after developing hypercalcemia, were then killed and bone marrow plasma from the long bones were obtained, concentrated, and assayed for bone-resorbing activity. Bone marrow plasma from ARH-77 mice induced significant bone resorption in the fetal rat long bone resorption assay when compared with controls (percentage of total 45Ca released = 35% +/- 4% v 11% +/- 1%). Histologic examination of tissues from the ARH-77 mice showed infiltration of myeloma cells in the liver and spleen and marked infiltration in vertebrae and long bones, with loss of bony trabeculae and increased OCL numbers. Interestingly, cultures of ARH-77 mouse bone marrow for early OCL precursors (colony-forming unit-granulocyte-macrophage [CFU-GM]) showed a threefold increase in CFU-GM from ARH-77 marrow versus controls (185 +/- 32 v 40 +/- 3 per 2 x 10(5) cell plated). Bone-resorbing human and murine cytokines such as interleukin-6 (IL-6), IL-1 alpha or beta, TGF-alpha, lymphotoxin, and TNF alpha were not significantly increased in ARH-77 mouse sera or marrow plasma, compared with control mice, although ARH-77 cells produce IL-6 and lymphotoxin in vitro. Conditioned media from ARH-77 cells induced significant bone resorption in the fetal rat long bone resorption assay when compared with untreated media (percentage of total 45Ca released = 22% +/- 2% v 11% +/- 1%). This effect was not blocked by anti-IL-6 or antilymphotoxin (percentage of total 45Ca released = 19% +/- 1% and 22% +/- 1%, respectively). Thus, we have developed a model of human multiple myeloma bone disease that should be very useful to dissect the pathogenesis of the bone destruction in multiple myeloma.
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PMID:Development of an in vivo model of human multiple myeloma bone disease. 860 40

C57BL/6 human interleukin-6 (IL-6) transgenic mice develop mesangial proliferative glomerulonephritis with massive IgG1 plasmacytosis and die of renal failure in early life. To test whether the IL-6 overexpression could cause development of mesangial proliferative glomerulonephritis without plasmacytosis or promote proliferation of immature B cells that have not undergone immunoglobulin gene rearrangement, the IL-6 transgene was introduced into mice with severe combined immunodeficiency (SCID). In the immunocompetent littermate IL-6 transgenic mice, there were various symptoms such as plasmacytosis, nephropathy, anemia, and thrombocytosis, accompanied by marked increases in serum IL-6 levels as they aged. All these mice died by 25 weeks of age. In contrast, the SCID-IL-6 transgenic mice had no such abnormalities, except certain hematological changes, although the transgene was expressed in various tissues. In these mice, the serum IL-6 levels were 10- to 15-fold higher than those in the nontransgenic mice, and they remained constant throughout their lives. Furthermore, there were no signs of lymphoid development. This study demonstrates that deregulation of IL-6 expression does not stimulate cell growth or differentiation of immature B cells, and thus does not result in plasmacytosis and age-related increases in IL-6 production, and also does not generate mesangial proliferative glomerulonephritis.
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PMID:Interleukin-6 overexpression cannot generate serious disorders in severe combined immunodeficiency mice. 900 Apr 79

The effects Lactobacillus casei YIT9108 (LC 9018) on antitumor activity and cytokine production in Meth A fibrosarcoma (Meth A)-bearing BALB/c mice were examined. Intrapleural (i.pl.) administration of LC 9018 was effective in prolonging the survival of Meth A-bearing mice, and frequently cured mice of the tumor. However, the results also indicated that the effect of LC 9018 was in part inhibited in mice treated with anti-CD3 or anti-CD8 antibody, but not affected in anti-CD4 antibody-treated mice. In contrast, LC 9018 had little effect on Meth A-bearing SCID or nude mice. These results demonstrated that CD8+ T cells participated in prolonging the survival of Meth A-bearing mice. Moreover, the examination of the production of several cytokines revealed that the production of interferon-gamma and interleukin-6 was, in particular, augmented in the exudated fluid of the thoracic cavity in BALB/c mice injected with LC 9018 i.pl. These results suggested that i.pl. administration of LC 9018 induced those cytokines which had the potential to activate the thoracic macrophages or proliferate the thoracic lymphocytes to the cytotoxic T cells. Taken together, these findings demonstrated that the prolonging effects on survival by i.pl. administration of LC 9018 depended on CD8+ T cells, and the i.pl. administration of LC 9018 into i.pl. Meth A-bearing mice induced several cytokines which participated in the subsequent immunoresponses.
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PMID:Effects on antitumor activity and cytokine production in the thoracic cavity by intrapleural administration of Lactobacillus casei in tumor-bearing mice. 900 21

Interleukin-6 (IL-6) was found to function as a late-acting killer helper factor in the differentiation of CTLs. In the model of tumor-bearing mice, the systemic administration of recombinant IL-6 was found to mediate the antitumor effect on the immunogenic murine tumors via the in vivo induction of murine CTLs but not on the poorly immunogenic murine tumors in our previous study. However, an in vivo experimental model capable of analyzing the anti-human tumor effect via the in vivo induction of human CTLs has not yet been established. Therefore, in the present study, severe combined immunodeficient mice were given human peripheral blood lymphocytes (SCID-PBL/hu), and thereafter human tumor cells were administered i.p. into these SCID-PBL/hu mice as a model of human patients with cancer. When these SCID-PBL/hu mice bearing allogeneic human CESS B blastoid tumor cells were treated in vivo with recombinant adenovirus vector expressing IL-6 cDNA, both the induction of CD8+ human CTLs against CESS cells in the spleen cells and peritoneal exudate cells and a prolongation in the survival of these mice were observed. Furthermore, SCID-PBL/hu mice were given peripheral blood lymphocytes from patients with cancer (gastric or rectal cancers) and autologous human tumor cells. The in vivo administration of recombinant adenovirus vector expressing IL-6 cDNA induced CD8+ human CTLs specific for autologous human tumor cells from human precursor T cells. The in vivo injection of the IL-6 gene also inhibited growth and metastasis in autologous human cancers. Based on the above findings, the experimental model using SCID-PBL/hu mice and the IL-6 gene delivered in vivo by an adenovirus vector might therefore provide a new strategy capable of analyzing an anti-human tumor effect and the in vivo induction of human CTLs by cytokine gene therapy without using the human body.
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PMID:The anti-human tumor effect and generation of human cytotoxic T cells in SCID mice given human peripheral blood lymphocytes by the in vivo transfer of the Interleukin-6 gene using adenovirus vector. 910 22


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