ABSTRACT
BACKGROUND: STAT3 phosphorylation is associated with the neoplastic state in many types of cancer, including prostate cancer. We investigated the role of IL-6 signaling and phosphorylation of STAT3 in 2 rat prostatic epithelial lines. NRP-152 and NRP-154 cells were derived from the same rat prostate, yet the NRP-152 cells are not tumorigenic while the NRP-154 cells are tumorigenic. These lines are believed to represent 2 of the stages in the development of prostate cancer, hyperplasia and neoplasia. Differences in signaling pathways should play a role in the 2 phenotypes, hyperplastic and neoplastic. METHODS: We looked at the phosphorylation state of STAT3 by intracellular flow cytometry, using phospho-specific antibodies to STAT3. We used the same method to examine IL-6 production by the cell lines. We also measured apoptosis by binding of fluorescent annexin V to the cells. RESULTS: Although both cells lines made IL-6 constitutively, phosphorylated-STAT3 was present in untreated NRP-154 cells, but not in NRP-152 cells. Treatment with dexamethasone inhibited the IL-6 production of NRP-152 cells, but enhanced that of NRP-154 cells. Treatment with the JAK2 inhibitor AG490 induced apoptosis in NRP-152, but not NRP-154 cells. CONCLUSIONS: We conclude from these experiments that STAT3 activity plays a role in the phenotype of NRP-154 cell, but not NRP-152 cells. The significance of alternative IL-6 signaling pathways in the different phenotypes of the 2 cell lines is discussed.
Subject(s)
DNA-Binding Proteins/physiology , Epithelial Cells/metabolism , Epithelial Cells/pathology , Interleukin-6/physiology , Prostatic Hyperplasia/pathology , Prostatic Intraepithelial Neoplasia/pathology , Proto-Oncogene Proteins , Signal Transduction/physiology , Trans-Activators/physiology , Animals , Anti-Inflammatory Agents/pharmacology , Apoptosis/drug effects , Cell Line , DNA-Binding Proteins/chemistry , Dexamethasone/pharmacology , Enzyme Inhibitors/pharmacology , Epithelial Cells/chemistry , Epithelial Cells/enzymology , Interleukin-6/biosynthesis , Janus Kinase 2 , Male , Phenotype , Phosphorylation , Prostatic Hyperplasia/enzymology , Prostatic Hyperplasia/genetics , Prostatic Hyperplasia/metabolism , Prostatic Intraepithelial Neoplasia/enzymology , Prostatic Intraepithelial Neoplasia/genetics , Prostatic Intraepithelial Neoplasia/metabolism , Protein-Tyrosine Kinases/antagonists & inhibitors , Rats , Receptors, Interleukin-6/biosynthesis , STAT3 Transcription Factor , Trans-Activators/chemistry , Tumor Cells, Cultured , Tyrphostins/pharmacologyABSTRACT
An estimated 30% of cancer deaths are attributed to cachexia and its consequences. Cachexia (wasting syndrome) is the hypercatabolism of the body's carbon sources, proteins and lipids, for conversion into energy. It is induced by a variety of pathological conditions, including cancer. Among the inflammatory responses to cancer is the synthesis of cytokines, including IL-6 and related cytokines. These cytokines have been found to induce cachexia by altering metabolism of lipids and proteins. IL-6-like cytokines have been found to inhibit lipid biosynthesis by adipocytes, which increased the rate of lipid catabolism. Others have described the atrophy and increased catabolism of muscle protein due to IL-6. A cytokine closely-related to IL-6 is leptin, which plays a major role in lipid metabolism under normal conditions. The role of leptin in pathological conditions such as cancer cachexia has not yet been fully elucidated. Detailed mechanistic information about the induction of cancer cachexia by IL-6-like cytokines requires more research.
Subject(s)
Cachexia/metabolism , Interleukin-6/immunology , Neoplasms/complications , Animals , Cachexia/complications , Cachexia/immunology , Humans , Inflammation/immunology , Inflammation/metabolism , Interleukin-6/biosynthesis , Leptin/metabolism , Lipid Metabolism , Lipids/biosynthesis , Mice , Muscle Proteins/metabolism , Neoplasms/immunology , Neoplasms/metabolismABSTRACT
The development of cancer cachexia has been linked to cytokines related to interleukin6 (IL-6). We examined the kinetics of IL-6, IL-11, oncostatinM (OSM) and leukaemia inhibitory factor (LIF) induction in the splenocytes of tumour-bearing mice. Using a lung carcinoma line, which grows in C57BL/6J mice, we observed that when the tumour grew and cachexia was observed, the splenocytes produced IL-6, IL-11, and OSM, but not LIF. Cytokine expression was observed within 1 week (day 3 for IL-6 and IL-11, and day 1 for OSM) of administration of tumour cells, and was observed in splenocytes without tumour metastases to the spleen. Cytokine expression preceded cachexia (determined by changes in serum triglyceride levels and decrease in epididymal fat-pad weights) development by over 1 week. Exogenous administration of IL-11 resulted in the accelerated onset of cachexia, compared to control protein treatment, but without an effect on the tumour burden. In vivo treatment with a neutralizing dose of anti-OSM antibody inhibited the triglyceride dysregulation only until the synthesis of IL-6 and IL-11 began in the spleen (day 3). Afterward, IL-6 and IL-11 induced lipid catabolism in the absence of functional OSM. We conclude from the data described above that cachexia developed due to a systemic cytokine response induced by a tumour burden, and that IL-6-like cytokines contributed independently to lipid hypercatabolism in the aetiology of cancer cachexia.
Subject(s)
Cachexia/metabolism , Cytokines/metabolism , Interleukin-6/metabolism , Neoplasms/complications , Spleen/metabolism , Animals , Blotting, Western , Flow Cytometry , Growth Inhibitors/metabolism , Interleukin-11/metabolism , Kinetics , Leukemia Inhibitory Factor , Lymphokines/metabolism , Male , Mice , Mice, Inbred C57BL , Neoplasm Transplantation , Oncostatin M , Peptides/metabolism , Protein Binding , Recombinant Proteins/metabolism , Spleen/cytology , Time FactorsABSTRACT
Myeloma is a neoplasm thought to "home" to bone marrow. However, evidence for bone-marrow-specific receptors or adhesion molecules expressed on myeloma cells is scanty. Initial myeloma expansion is thought to be due to IL-6 and/or related cytokines. Previous determinations of cytokine expression in bone marrow were performed on bone marrow stromal lines; these findings may not reflect the constitutive pattern of expression in situ. Intracytoplasmic staining for IL-6-like cytokines revealed constitutive expression of some factors in the bone marrow of normal mice, but not spleens. Spleens of myeloma-transplanted SCID mice expressed IL-6-like cytokines, indicative of induction of expression by myeloma. Some cytokines expressed in bone marrow induced myeloma proliferation in the presence of dexamethasone, demonstrating dependence of the myeloma on these cytokines. Our data imply that, rather than "homing" to bone marrow, myeloma cells proliferated within marrow cavities more than in other organs because of growth factors constitutively expressed by bone marrow cells. As myeloma progressed, we observed the induction of growth factor expression in spleen cells. Furthermore, because cytokines other than IL-6 may induce myeloma cell proliferation, therapy aimed at neutralizing IL-6 may not be the most effective method to treat this disease. These findings have implications for both the pathophysiology and therapy of multiple myeloma.
Subject(s)
Bone Marrow/metabolism , Interleukin-6/biosynthesis , Multiple Myeloma/metabolism , Multiple Myeloma/physiopathology , Animals , Antineoplastic Agents, Hormonal/pharmacology , Cell Division/drug effects , Cell Separation , Dexamethasone/pharmacology , Dose-Response Relationship, Drug , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Growth Inhibitors/biosynthesis , Growth Inhibitors/pharmacology , Humans , Immunohistochemistry , Interleukin-11/biosynthesis , Leukemia Inhibitory Factor , Lymphokines/biosynthesis , Male , Mice , Mice, SCID , Neoplasm Transplantation , Oncostatin M , Peptides/pharmacology , Spleen/metabolism , Tumor Cells, CulturedABSTRACT
A human myeloma line was used to create a model of human multiple myeloma in vivo that would reproduce the pathophysiology of the disease, including the cachexia associated with cancer. Unirradiated severe combined immunodeficient (SCID) mice were used as surrogate hosts for in vivo experiments that allowed the effects of autocrine (human) verus paracrine (murine) cytokines on the development of myeloma to be studied. Serum levels of human paraprotein increased over time and with the number of cells transplanted. Transplanted mice developed major syndromes, cachexia and paralysis (due to invasion of bones by myeloma cells), associated with multiple myeloma. Analyses of serum samples obtained from transplanted mice revealed that when the mice were terminal, total serum protein decreased on average by 20%, whereas serum triglycerides decreased on average by 50%. These data indicate the mice were cachectic, which was confirmed by necropsy. The mice had low but measurable levels of both human and murine interleukin (IL)-6, soluble IL-6 receptor, and murine IL-10 in their sera. The presence of these cytokines and the IL-6 receptor in sera are also characteristics of human myeloma in patients. Since human cells do not respond to murine IL-6, it was possible to demonstrate clearly the importance of autocrine IL-6 in establishing myeloma in situ. By reproducing both the hallmarks of a cancer as well as the accompanying paraneoplastic syndromes, this model should be useful in designing more effective therapies for both the primary cancer as well as the accompanying secondary diseases.
Subject(s)
Disease Models, Animal , Multiple Myeloma/physiopathology , Animals , Cachexia , Cell Transplantation , Cytokines/blood , Humans , Kinetics , Male , Mice , Mice, SCID , Multiple Myeloma/pathology , Neoplasm Transplantation , Syndrome , Time Factors , Tumor Cells, CulturedABSTRACT
IL-6 has many novel activities both within the adaptive immune system and without. It has therapeutic potential in acute inflammation, such as toxic or septic shock, and it is a potential target for cachexia, multiple myeloma, and osteoporosis. Further work on these aspects of IL-6 biology should yield new insight into the possibility of IL-6 both as a therapeutic agent and as a target for antagonists.
Subject(s)
Interleukin-6/physiology , Animals , Anti-Inflammatory Agents/pharmacology , Bone Resorption/etiology , Bone Resorption/immunology , Cachexia/etiology , Cachexia/immunology , Cytokines/genetics , Cytokines/pharmacology , Cytokines/physiology , Humans , Interleukin-6/genetics , Interleukin-6/pharmacology , Neutralization Tests , Osteoclasts/physiologyABSTRACT
BALB/By mice given doses of D-galactosamine plus Staphylococcus aureus enterotoxin B die within 48 h of administration. The cause of death is a syndrome much like toxic shock syndrome in humans. We used this model to investigate the role of two cytokines, interleukin 6 and interleukin 11, which share the signal transducing subunit, gp130, of their respective receptors. We observed that pretreatment of mice with antibody to interleukin 6 increased mortality from 55% to nearly 90% (P < 0.001), while pretreatment with either cytokine reduced death. The protection was dose dependent; however, interleukin 6 was about 10-fold more potent that interleukin 11. These data indicate that endogenous interleukin 6 plays a protective role in attenuating acute inflammatory responses; furthermore, interleukin 6 and interleukin 11 can abrogate T-cell activation due to triggering by superantigen. A possible clinical role for these cytokines in the treatment of toxic shock merits further investigation.
Subject(s)
Enterotoxins/toxicity , Interleukin-11/therapeutic use , Interleukin-6/therapeutic use , Shock, Septic/mortality , Shock, Septic/therapy , Staphylococcus aureus/pathogenicity , Animals , Male , Mice , Mice, Inbred BALB C , Tumor Necrosis Factor-alpha/physiologyABSTRACT
NBXFO hybridoma cells produced macrophage colony-stimulating factor (M-CSF), which stimulated the growth of murine bone marrow-derived macrophages with potent suppressor activity. These macrophages suppressed lymphocyte responses to mitogens and antigens in a dose-dependent manner. Using a transwell chamber, we demonstrated that macrophages needed physical contact with the lymphocytes to suppress lymphocyte proliferation on day 1 in the concanavalin A mitogen reaction. In addition, no soluble suppressor factor was detected at that time. The number of lymphocytes disappeared with time when they were cocultured with the macrophages. Electron microscopy revealed that the macrophage phagocytosized the lymphocytes after 7 1/2 h. Dextran sulfate, heparan, and fucoidan prevented the macrophages from suppressing the lymphocytes. This phenomenon resembles the human disease sinus histiocytosis, also called Rosai-Dorfman disease, in which macrophages (histiocytes) phagocytosize autologous lymphocytes; occasionally, this disease is associated with immunological abnormalities. Thus we believed that macrophage-activating cytokines, such as M-CSF, may stimulate macrophages to phagocytose lymphocytes in vivo.
Subject(s)
Histiocytosis, Sinus/etiology , Lymphocyte Activation , Macrophage Activation/drug effects , Macrophage Colony-Stimulating Factor/pharmacology , Macrophages/physiology , Phagocytosis , Animals , Cell Communication , Cell Line , Dose-Response Relationship, Drug , Immune Tolerance , Male , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Mice, Inbred DBAABSTRACT
The neonatal spleen:myeloma hybridoma cell, NBXFO, with immunosuppressive properties supported rodent hematopoietic colony formation. We identified this hybridoma to be an undifferentiated fibroblast that produced macrophage colony-stimulating factor (M-CSF). The bone marrow cells that grew in the presence of the NBXFO supernate were macrophages and were immunosuppressive towards lymphocytes. Neutralizing anti-M-CSF antibody partially inhibited the actions of the neonatal splenic suppressor cells. Neonatal splenocytes, but not the other parental cell line, FO, induced macrophage colony formation, possessed surface-associated M-CSF, and possessed M-CSF-specific transcripts. Therefore, we believe that the M-CSF-producing phenotype was contributed by a fibroblastic stromal cell and that these stromal cells could be responsible for the in situ generation of neonatal splenic suppressor cells.
Subject(s)
Animals, Newborn/immunology , Hybridomas/immunology , Spleen/immunology , Animals , Hybridomas/metabolism , Laminin/analysis , Macrophage Colony-Stimulating Factor/analysis , Macrophage Colony-Stimulating Factor/biosynthesis , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Inbred DBA , RatsABSTRACT
Oncostatin M was found to stimulate the IL-6-addicted hybridoma line B9. Leukaemia inhibitory factor did not stimulate proliferation of this line. Both of these factors bind to the gp130 of the IL-6 receptor. In another cell line that is stimulated by LIF (DA.1), neither IL-6 nor oncostatin M stimulated proliferation. Previously it had been thought that the gp130 alone is sufficient to bind ligand and transduce signal and that oncostatin M could bind to and activate the LIF receptor, but these data show this is not always the case. Mice primed with Pristane were found to have IL-6 in their sera and peritoneal fluid only at a few time points following Pristane treatment; this was determined by IL-6-specific ELISA. When the same samples were analysed on IL-6-addicted B9 cells, stimulatory activity was found at all time points. When the Pristane-primed samples were assayed for oncostatin M activity in the A375 melanoma assay, there was oncostatin M activity at various time points. IL-6 did not have activity on the A375 cells. These data indicate that oncostatin M play a role in the generation of plasmacytoma in vivo.
Subject(s)
Cell Division/drug effects , Interleukin-6/pharmacology , Peptide Biosynthesis , Peptides/pharmacology , Plasmacytoma/pathology , Animals , Carcinogens/toxicity , Cell Line , Dose-Response Relationship, Drug , Growth Inhibitors/biosynthesis , Growth Inhibitors/pharmacology , Humans , Hybridomas , Interleukin-6/biosynthesis , Kinetics , Leukemia Inhibitory Factor , Lymphokines/pharmacology , Male , Melanoma , Mice , Mice, Inbred BALB C , Oncostatin M , Terpenes/toxicity , Time Factors , Transfection , Tumor Cells, CulturedABSTRACT
C57BL/6J mice given low doses of lipopolysaccharide (LPS) (100 ng per mouse) plus D-galactosamine (8 mg per mouse) die within 24 h following LPS administration. We used this septic shock model to confirm the role of tumor necrosis factor in mortality using a monoclonal antibody to tumor necrosis factor to prevent lethality. Furthermore, we demonstrated that interleukin 6, rather than playing a lethal role, protected mice against death in this septic shock model. Antibody to interleukin 6 did not affect the fatal outcome in this low-LPS-dose model. However, pretreatment with antibody to tumor necrosis factor did protect the mice against death, in a dose-dependent manner. Moreover, mortality was enhanced by pretreatment with antibody to interleukin 6 when tumor necrosis factor was partly limited by anti-tumor necrosis factor treatment. Mortality was significantly reduced by pretreatment with both recombinant interleukin 6 and low doses of antibody to tumor necrosis factor; in the absence of the low dose of antibody to tumor necrosis factor, interleukin 6 alone did not confer any protection. These data demonstrate in vivo antagonistic activities of tumor necrosis factor and interleukin 6 and show that interleukin 6 can play a protective role against death from septic shock.
Subject(s)
Galactosamine/toxicity , Interleukin-6/pharmacology , Lipopolysaccharides/toxicity , Shock, Septic/drug therapy , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Animals , Male , Mice , Mice, Inbred C57BL , Recombinant Proteins/therapeutic useABSTRACT
NFS60, a murine leukemia cell line, responds to both interleukin 3 and 6 by proliferating, apparently by different signal transduction pathways. Although stimulation by both cytokines increases the uptake of 3H-arachidonic acid, the response to IL-6 was much faster. Furthermore, the effect of various arachidonic acid metabolites on the response to cytokine was different. PGE2 inhibited IL-6-induced proliferation and potentiated the response to IL-3. Additionally the G proteins which coupled the IL-3 and IL-6 receptor to the proliferative response are probably different, based on the ability of cholera toxin to inhibit the IL-3 but not the IL-6 response. These data are evidence of two pathways of signal transduction.
Subject(s)
Cytokines/pharmacology , Signal Transduction/drug effects , Animals , Arachidonic Acid/metabolism , Calcimycin/pharmacology , Cell Division/drug effects , Cyclic AMP/metabolism , GTP-Binding Proteins/metabolism , Interleukin-3/pharmacology , Interleukin-6/pharmacology , Prostaglandins/pharmacology , Protein Kinase C/metabolism , Signal Transduction/physiology , Tumor Cells, Cultured/drug effects , Virulence Factors, Bordetella/pharmacologyABSTRACT
Mometasone furoate (9 alpha, 21 dichloro-11 beta, 17 alpha dihydroxy-16 alpha methyl-1,4 pregnadiene-3, 20 dione-17-[2'] furoate) was an unexpectedly potent inhibitor of the in vitro production of three inflammatory cytokines, IL-1(1), IL-6, and TNF-alpha. The potency of mometasone furoate in inhibiting cytokine production was compared to that of hydrocortisone, betamethasone, dexamethasone, and beclomethasone. IL-6 and TNF-alpha were both produced by WEHI-265.1 (murine myelomonocytic leukemia) cells following stimulation by lipopolysaccharide (LPS). Twenty-four hours after stimulation by LPS, the cell-free supernatant fluids were removed. Their cytokine content was analyzed using ELISAs specific for each cytokine. IL-1 synthesis was induced in the harvested peritoneal macrophages of BALB/c mice by incubation with LPS for twenty-four hours. The IL-1 content in the cell-free supernatant fluids was determined by the thymocyte-costimulator bioassay. Using these systems, mometasone furoate was found to be the most potent steroid tested for inhibiting the production of the three cytokines. The IC50's were 0.05 nM (IL-1), 0.15 nM (IL-6), and 0.25 nM (TNF-alpha). The inhibition of the production of proinflammatory mediators by extremely low concentrations of mometasone furoate suggests that this steroid should be highly effective in various disorders.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Interleukin-1/antagonists & inhibitors , Interleukin-6/antagonists & inhibitors , Pregnadienediols/pharmacology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Administration, Topical , Animals , Glucocorticoids , Interleukin-1/biosynthesis , Interleukin-6/biosynthesis , Mice , Mometasone Furoate , Tumor Cells, Cultured , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
Bone resorption in vitro and in vivo can be induced by interleukin 1 (IL 1) and tumor necrosis factor (TNF), both of which are potent inflammatory cytokines. Additionally, there are other factors produced by cells which can active osteoclasts. Because diverse factors are involved in bone resorption, we examined the role of two other inflammatory cytokines, IL 3 and IL 6. IL 3 has been shown to induce the formation of osteoclast-like cells from precursors, while IL 6 is a potent mediator of inflammatory responses. Osteoclast activity in neonatal mouse calvaria was measured as 45Ca released into the supernatant fluid following a 48 hr incubation period with cytokine. Our results show that while parathyroid hormone (PTH) and IL 1 are potent inducers of bone resorption, neither IL 3 nor IL 6 displayed such activity.
Subject(s)
Bone Resorption , Interleukin-3/pharmacology , Interleukin-6/pharmacology , Animals , Animals, Newborn , Calcium/metabolism , Dose-Response Relationship, Drug , In Vitro Techniques , Interleukin-1/pharmacology , Mice , Parathyroid Hormone/pharmacologyABSTRACT
SK&F 86002, a mixed cyclooxygenase-lipoxygenase inhibitor, was examined for its effects on helper T cell functions. The drug was found to inhibit concanavalin A-induced mitogenesis of splenic T cells (IC50 = 13 microns), the mixed lymphocyte response (IC50 = 16 microM), and proliferation of antigen specific T cells (cloned line, IC50 = 11 microM; uncloned line, IC50 = 13 microM). In contrast, another mixed cycloxygenase-lipoxygenase inhibitor, BW775c, did not have such effects at non-cytotoxic levels. These T cell functions are believed to be dependent on the effects of elaborated IL-1. SK&F 86002 has been shown to inhibit the production of mature IL-1 (IC50 = 1 microM), possibly accounting for the anti-inflammatory effects of the drug in rheumatoid arthritis models. In an in vivo model of contact sensitivity, SK&F 86002 was able to inhibit mouse footpad swelling, demonstrating additional anti-inflammatory activity. As an inhibitor of IL-1 synthesis or release, SK&F 86002 may be useful for the treatment of T cell-dependent inflammation.
Subject(s)
Imidazoles/pharmacology , T-Lymphocytes, Helper-Inducer/drug effects , Thiazoles/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antigens , Dermatitis, Contact/drug therapy , Dinitrophenols/immunology , In Vitro Techniques , Interleukin-1/biosynthesis , Lymphocyte Activation/drug effects , Lymphocyte Culture Test, Mixed , Mice , Mice, Inbred Strains , Serum Albumin, Bovine/immunology , T-Lymphocytes, Helper-Inducer/immunologyABSTRACT
IL-3, a cytokine with hematopoietic differentiating capability, induced murine bone marrow cells to differentiate into cells resembling osteoclasts. The cells resulting from treatment with IL-3 were multi-nucleated and demonstrated tartrate-resistant acid-phosphatase activity, as do resident osteoclasts found in bone. IL-3-induced osteoclast-like cell development in the absence of serum-derived vitamin D metabolites, and a mAb that inhibited IL-3-induced proliferation of an addicted cell line also inhibited the development of osteoclasts in the presence of IL-3. The same Ab had no effect on 1 alpha, 25-dihydroxyvitamin D3-induced differentiation of osteoclasts. This newly described function of IL-3 may indicate a role for activated T cells in the bone resorption seen with rheumatoid arthritis.
Subject(s)
Bone Marrow/physiology , Cell Differentiation , Hematopoietic Stem Cells/physiology , Interleukin-3/pharmacology , Osteoclasts/physiology , Acid Phosphatase , Animals , Antibodies, Monoclonal/pharmacology , Bone Marrow/enzymology , Bone Marrow/immunology , Cell Differentiation/drug effects , Cells, Cultured , Growth Inhibitors/immunology , Hematopoietic Stem Cells/enzymology , Hematopoietic Stem Cells/immunology , Interleukin-1/pharmacology , Interleukin-2/pharmacology , Interleukin-3/immunology , Male , Mice , Osteoclasts/enzymology , Osteoclasts/immunology , Recombinant Proteins/pharmacology , TartratesABSTRACT
Macrophages are fully differentiated cells that do not synthesize an extracellular matrix and do not contract; they do, however, produce substances that modify the behavior and functions of other cells, particularly those involved in the inflammatory and immune responses. Since macrophages are a ubiquitous component of periretinal membranes, we sought to determine whether they modulate proliferation and/or migration of retinal pigment epithelial (RPE) cells, functions that may be essential for the development of proliferative vitreoretinopathy (PVR). Using an in vitro assay, we found that macrophage supernatant contains factors that stimulate proliferation and migration of cultured human RPE cells. Since interleukin-1 (IL-1) is a product of activated macrophages that modulates a number of cellular functions, we also examined its effect on RPE proliferation and migration. We found that IL-1 increased migration but did not affect proliferation, and thus could not duplicate the effect of macrophage supernatant. Injection of activated macrophages into the vitreous of rabbits which had a retinal hole stimulated RPE cell proliferation in the area of the retinal hole, where the RPE cells were exposed. These findings suggest the ability of macrophages to modulate functions of RPE cells that are thought to be critical for the development of PVR. Macrophages may thus be an important part of the vitreous environment that favors the development of PVR.
Subject(s)
Macrophages/physiology , Pigment Epithelium of Eye/cytology , Animals , Cell Division/drug effects , Cell Movement/drug effects , Cells, Cultured , Chemotaxis/drug effects , Female , Humans , Interleukin-1/pharmacology , Male , RabbitsABSTRACT
The NBxFO factor was obtained from the supernatant liquids of neonatal spleen: myeloma fusions. Previously it had been shown that this factor could inhibit the proliferative response of alloreactive T cell lines. In this study the factor was found to inhibit the MLR of the parent species (mouse) as well as the MLRs of humans and rats. Thus, the NBxFO factor has activity that is not species-specific. Furthermore, the factor was found to inhibit the lectin-induced mitogenesis of these 3 species. Gel chromatography revealed that the moleclar weight of the molecule responsible for suppressing human lymphocyte mitogenesis is the same as previously determined for suppression of mouse proliferative responses.