Interleukin-10 is a growth factor for human myeloma cells by induction of an oncostatin M autocrine loop (original) (raw)
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Interleukin-10 induces interleukin-11 responsiveness in human myeloma cell lines
FEBS Letters, 1995
Interleukin (IL)-6-dependent human myeloma cell lines (HMCL) can be reproducibly obtained from patients with multiple myeloma and terminal disease. The growth of some of these HMCL can also be supported by IL-11. We show that IL-11-responsive, but not-unresponsive, HMCL expressed the gene of human IL-11 receptor (IL-I1R) and produced an autocrine IL-10. All HMCL expressed the IL-10 receptor. In addition, IL-10 induced IL-11R gene expression and conferred IL-11 responsiveness on unresponsive HMCL. The ability of I-IMCL to produce IL-10 was strictly correlated with the capacity of the original patient's myeloma cells to produce IL-10 or not, and with the presence or absence of IL-10 in the patient's plasma.
PubMed, 1996
The in vivo production of interleukin (IL)-10, IL-6, IL-2, and tumor necrosis factor (TNF)-alpha in tumor samples was investigated by immunohistochemistry in 54 non-Hodgkin's lymphomas (NHLs). Respectively, 55, 89, 23, and 29% of tumor samples were found positive for IL-10, IL-6, IL-2, and TNF-alpha expression by immunohistochemistry. Using reverse transcription-PCR, the mRNA of IL-10 and IL-6 were detectable in all samples tested and in 90 and 34% of the samples for TNF-alpha and IL-2, respectively. In 13 patients, fresh tumor tissue was available for B NHL cell purification with Dynabeads. IL-10, IL-6, IL-2, and TNF-alpha were detectable in the supernatant of 38, 100, 0, and 23% of purified tumor cell preparations (PTCPs), respectively. All patients with detectable IL-10 in culture had increased serum IL-10. IL-6 production by tumor cells and serum IL-6 levels were also found to be highly correlated (P < 0.0001). This suggests that tumor cells are a major source of serum IL-1O and IL-6 in these patients. Exogenous IL-10, IL-6, IL-2, and TNF-alpha significantly enhanced the [3H]thymidine uptake in 13 of 13 (100%), 5 of 13 (38%), 9 of 13 (69%), and 2 of 10 (20%) PTCPs costimulated with anti-CD40, respectively. IL-2, IL-6, and TNF-alpha synergized with IL-10 in 54, 23, and 30% of PTCPs. The combination of IL-10, IL-2, and IL-6 induced the maximal level of proliferation in 12 (92%) of 13 PTCPs. CD40 ligand mRNA expression was also detectable in vivo using reverse transcription-PCR in 28 of the 29 (97%) tumor samples tested, including 11 of those tested for [3H]thymidine incorporation. These results show that IL-1O, IL-6, IL-2, and TNF-alpha are produced in NHL tumors and may cooperate in vivo to increase NHL cell proliferation.
European cytokine network, 2000
We investigated the serum concentration of the interleukin-10 (IL-10), along with cytokines of interleukin-6 (IL-6) family (IL-6, IL-11 and oncostatin M - OSM), as well as soluble receptor for IL-6 (sIL-6R), in 121 patients with multiple myeloma (MM) and 28 healthy subjects. We studied the interactions between IL-10 and other cytokines, and the receptor. The correlation between IL-10 and some clinical and laboratory parameters associated with the disease activity were also analysed. The IL-10 was detectable in all patients with multiple myeloma and in all controls. The IL-10 concentration was significantly increased in myeloma patients compared with healthy persons (mean - 7.09 and 2.1 pg/ml, respectively) (p = 0.008). The level of IL-10 correlated positively with the advanced stage of disease estimated according to the Salmon and Durie classification (I versus III stage - p = 0.03). Higher values of IL-10 were found in patients with the light chain disease, hypercalcaemia, and corr...
Interleukin-10 Inhibits Tumor Metastasis, Downregulates MHC Class I, and Enhances NK Lysis
Cellular Immunology, 1997
IL-2-mediated induction of CTL precursors (2, 3) and is chemotactic for CD8/ cells (4). Importantly, this cy-We have engineered highly aggressive murine mamtokine stimulates human NK cell functions (5, 6). mary tumor cell line 410.4 to express interleukin-10 Several laboratories have demonstrated that IL-10 (IL-10) and compared the behavior in vivo of these cells is a potent inhibitor of tumor growth and metastasis in to parental 410.4 and 410.4 transfected with the control plasmid (410.4-neo). Transplantation of parental 410.4 animal models (7-13).
Antimetastatic and Antitumor Activities of Interleukin 10 in a Murine Model of Breast Cancer
JNCI Journal of the National Cancer Institute, 1996
Background: Interleukin 10 (IL-10) is a potent immunoregulatory cytokine. It inhibits some cell functions, including T-helper (Thl) cell activity (i.e., interleukin 2 and interferon gamma production), and stimulates other functions such as natural killer (NK) activity. In mice, IL-10 suppresses tumorigenicity in a xenograft system using a nonmetastasizing hamster cell line. Purpose: We evaluated the antitumor and antimetastatic properties of IL-10 in syngeneic immunocompetent and immunocompromised murine hosts. Methods: Using the plasmids pBMGneo and pBMGneo.IL-10, we transfected the highly malignant murine mammary tumor cell lines 410.4 and 66.1 (transfectants designated as 410.4-IL10 and 66.1-IL10, respectively) to stably express IL-10 (2-100 U IL-10/2.5 x 10 5 cells per 48 hours). Tumorigenic and metastatic activities of the parent and transfected cells were measured in immunocompetent, syngeneic BALB/cByJ mice as well as in immunocompromised C.B-17/IcrCrl-SCID/BR and C.B-17/IcrCrl-SCID/Beige mice. Results: Tumor growth was completely inhibited following inoculation of 5 x 10 6 410.4-IL10 cells in immunocompetent, syngeneic BALB/cByJ mice. This inoculum contained 100 times the minimum cell number required for 100% tumor incidence. In contrast, tumor growth following the inoculation of parental 410.4 or 410.4-neo cells was progressive, resulting in death of animals from pulmonary metastases at days 40-50 after transplantation. The tumorigenicity of 66.1-IL10, compared with that of its parent cell line, was also significantly abrogated by IL-10 expression. Furthermore, in immunocompetent mice, the metastatic potential of both 410.4-IL10 and 66.1-IL10 was also completely inhibited. In immunocompromised C.B-17/IcrCrl-SCID/BR or C.B-17/IcrCrl-SCID/Beige mice, subcutaneous implants of 410.4-IL10 grew progressively, but growth was inhibited significantly in comparison to that produced by the parental 410.4 or 410.4-neo cells. In spite of the more limited efficacy of IL-10 against tumor growth in immunocompromised mice, spontaneous metastasis of 410.4-IL10 cells in C.B-17/IcrCrl-SCID/BR mice was inhibited by 90%. When NK activity was suppressed by asialoGMl ganglioside antibody in BALB/cByJ mice or in C.B-17/IcrCrl-SCID/Beige mice, the antimetastatic effect of IL-10 was lost. Conclusions: These data show for the first time that IL-10 is a potent antimetastatic agent that is effective in immunocompromised hosts. This effect thus appears to be relatively independent of T-cell function but is dependent on NK activity. In contrast, the inhibitory effect of IL-10 on tumorigenicity relies on T-cell function. Implications: Based on the recent observation of others that IL-10 has little toxicity when administered systemically to human volunteers and also on the findings of this study that it has antitumor and antimetastatic properties in mice, possible use of IL-10 in the treatment of human metastatic cancers deserves consideration.
In vivo production of interleukin-10 by malignant cells in AIDS lymphomas
European Journal of Immunology, 1992
Expression of the interleukin (IL)-10/BCRF1 gene was studied by in situ hybridization in tissue samples from acquired immunodeficiency syndrome (AIDS) lymphomas using a BCRF1 probe which also recognizes the human IL-10 sequence. Hybridization was detected in 8 out of 15 lymphomas. In contrast, the IL-10/BCRF1 gene expression was detected in only 1 out of 11 lymphomas from human immunodeficiency virus (HIV)-seronegative patients (p = 0.05). In AIDS lymphomas, the number of cells labeled with a BCRF1-specific probe was dramatically lower than that of cells labeled with the IL-10/BCRF1 probe. Thus, the IL-10 rather than the BCRF1 gene was expressed. Production of IL-10 was associated with that of IL-10 mRNA, as shown by immunodetection of the protein in numerous cells. In contrast, BCRF1-producing cells were rarely detected. Both in situ hybridization and immunochemical experiments indicated that malignant cells were involved in this IL-10 synthesis. IL-10 production in AIDS lymphomas was associated with the presence of Epstein-Barr virus (EBV) in lymphomatous cells (p = 0.02). As IL-10 is a potent growth factor for human B lymphocytes, these results suggest that IL-10 may stimulate the proliferation of malignant cells in an autocrine pathway in a number of AIDS lymphomas, and that EBV and HIV may synergistically trigger its production.
Interleukin 10 is a human T cell growth factor in vitro
Cytokine, 1995
Although interleukin (IL)-10 inhibited lymphocyte proliferation in mixed lymphocyte cultures (MLC) and blocked stimulation of alloreactive T cell clones (TCC) by peripheral blood mononuclear cells (PBMC), the cells surviving culture with IL-10 showed enhanced viability. A minority of IL-2-dependent T cell lines, moreover, incorporated tritiated thymidine when cultured with IL-10 alone; their proliferation with IL-10 was dose-dependent, prevented by addition of neutralizing antisera to IL-10 but not to IL-2 and/or IL-4 and observed both shortly (4 days) and later ( 7-10 days) after T cell allostimulation. Examination of the proliferative responses to IL-10 of a panel of TCC revealed heterogeneity of responsiveness: whereas only one of five CD8 ÷ TCR2 (T cell receptor ~, [~)-TCC proliferated with IL-10, three of five CD4 ÷ TCR2-TCC proliferated, one of them strongly. In contrast, all three TCR1 (~,5)-TCC tested responded to IL-10, albeit rather weakly. These results therefore suggest that in addition to its well-established inhibitory action on T cell activation, IL-10 may also exert positive influences on clonal expansion of subsets of preactivated T cells.
Translational Research in Cancer [Working Title]
Chronic inflammation can trigger events that would induce the malignant transformation of cells and carcinogenesis. Cytokines play a crucial role and can control the development and multiplication of cancerous cells. However, clinical data present controversy about the participation of these proteins in the establishment and development of cancer. Interleukin 10 (IL-10), a potent anti-inflammatory cytokine, has been the subject of multiple studies. Several studies have reported that IL-10 has pro-and antitumor effects. Elevated levels of IL-10 are associated with increased tumor growth with poor prognosis and drug resistance. However, this cytokine has both tumor-promoting and tumor-inhibiting properties. In vitro and in vivo studies report mechanisms by which IL-10 expression downregulates class I, which results in the control of the metastatic disease. IL-10 also inhibits tumorigenesis via downregulation of other cytokines. The variation observed could be the result of concentration ranges of this protein, genetic polymorphism, or both. The value obtained may serve as a biomarker indicative of tumor development and its prognosis.
Immunology, 2002
The aim of this study was to investigate the mechanisms by which interleukin-10 (IL-10) induces tumour growth in a mouse-melanoma model. A B16-melanoma cell line (B16-0) was transfected with IL-10 cDNA and three clones that secreted high (B16-10), medium and low amounts of IL-10 were selected. Cell proliferation and IL-10 production were compared in vitro, and tumour growth, percentages of necrotic areas, tumour cells positive for proliferating cell nuclear antigen (PCNA), IL-10 receptor (IL-10R) and major histocompatibility complex type I (MHC-I) and II (MHC-II), as well as in®ltration of macrophages, CD4 + and CD8 + lymphocytes and blood vessels were compared in vivo among IL-10-transfected and non-transfected tumours. Proliferation and tumour growth were greater for IL-10-transfected than for non-transfected cells (P<0. 001), and correlated with IL-10 concentration (ri0. 79, P<0. 006). Percentages of tumour cells positive for PCNA and IL-10R were 4. 4-and 16. 7-fold higher, respectively, in B16-10 than in B16-0 tumours (P<0. 001). Macrophage distribution changed from a diffuse pattern in non-transfected (6. 4t1. 7%) to a peripheral pattern in IL-10-transfected (3. 8t1. 7%) tumours. The percentage of CD4 + lymphocytes was 7. 6 times higher in B16-10 than in B16-0 tumours (P=0. 002). The expression of MHC-I molecules was present in all B16-0 tumour cells and completely negative in B16±10 tumour cells. In B16-0 tumours, 89t4% of the whole tumour area was necrotic, whereas tumours produced by B16-10 cells showed only 4. 3t6% of necrotic areas. IL-10-transfected tumours had 17-fold more blood vessels than non-transfected tumours (61. 8t8% versus 3. 5t1. 7% blood vessels/tumour; P<0. 001). All the effects induced by IL-10 were prevented in mice treated with a neutralizing anti-IL-10 monoclonal antibody. These data indicate that IL-10 could induce tumour growth in this B16-melanoma model by stimulation of tumour-cell proliferation, angiogenesis and immunosuppression.
Cancer research, 1997
Juvenile myelomonocytic leukemia (JMML) carries a poor prognosis. The endogenous production of cytokines by the JMML cells contributes to their growth and therapeutic resistance. Interleukin (IL)-4, IL-10, and IL-13 inhibit cytokine production in monocytes. We have now studied whether these cytokines can inhibit JMML cell cytokine production, thereby potentially reducing the malignant cell load in this disorder. We found that IL-10, but not IL-4 or IL-13, dose dependently inhibited JMML cell production of the hemopoietic growth factors granulocyte-macrophage colony-stimulating factor, tumor necrosis factor alpha, and IL-1beta. Similarly, IL-10, but not IL-4 or IL-13, suppressed JMML colony formation and cell viability. This was not due to the absence of receptors because we could detect mRNAs for the IL-4 and the IL-13 receptor alpha subunits and the IL-2 common gamma subunit in JMML cells. Furthermore, the receptors were active since both IL-4 and IL-13 up-regulated surface express...