Expression of interleukin 10 in human melanoma

Krüger‐Krasagakes, Sabine; Krasagakis, Konstantin; Garbe, Claus; Schmitt, Edgar; Hüls, Christoph; Blankenstein, Thomas; Diamantstein, Tibor

doi:10.1038/bjc.1994.469

Cited by 127 publications

(83 citation statements)

References 22 publications

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“…RT-PCR analysis of pure NHK, melanocytes, Langerhans cells and fibroblast suspensions provided conclusive proof that within normal epidermis only melanocytes were able to synthesize IL-10 mRNA. Our finding that melanocytes express IL-10 mRNA is in agreement with the observation of other investigators [45,46]. We and others [45] could not detect IL-10 protein in the supernatants of normal human melanocytes.…”

Section: Discussionsupporting

confidence: 94%

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In contrast to their murine counterparts, normal human keratinocytes and human epidermoid cell lines A431 and HaCaT fail to express IL-10 mRNA and protein

Teunissen¹,

Koomen²,

Jansen

et al. 1997

Clinical and Experimental Immunology

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SUMMARYIn mice, keratinocyte-derived IL-10 is up-regulated by ultraviolet-B (UVB) radiation and plays a major role in UVB-induced immunosuppression. The present study was designed to examine whether a comparable phenomenon can be detected in man. Freshly isolated or cultured normal human keratinocytes (NHK) and keratinocyte cell lines A431 and HaCaT were stimulated with graded doses of UVB (up to 200 J/m 2 ) or with a variety of other stimuli. RNA was extracted at various time points post-stimulation and analysed by reverse transcriptase-polymerase chain reaction (RT-PCR) using four different IL-10-specific primer pairs and RNA from monocytes or T cells as positive controls. We failed to detect IL-10 mRNA in NHK from 40 different donors (breast, abdomen, leg, scalp, foreskin) and in A431 and HaCaT cells, irrespective of the stimulation used and despite successful stimulation. Supernatants of NHK, A431 and HaCaT cultures were negative for IL-10 protein, as tested by four different ELISAs and a bioassay. Murine keratinocytes, stimulated under comparable conditions and tested by the same techniques, displayed a strong expression of IL-10 mRNA and protein. Remarkably, an IL-10 mRNA signal could be detected in NHK after a second round of PCR amplification. Because NHK suspensions are contaminated with Langerhans cells, melanocytes and possibly fibroblasts, we tested pure populations of each individual cell type to determine the origin of this IL-10 mRNA. Our results clearly indicate that NHK, Langerhans cells and fibroblasts fail to express IL-10 and that melanocytes are the principal source of IL-10 mRNA in normal human epidermis.

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Section: Discussionsupporting

confidence: 94%

“…Our finding that melanocytes express IL-10 mRNA is in agreement with the observation of other investigators [45,46]. We and others [45] could not detect IL-10 protein in the supernatants of normal human melanocytes. As yet it * Human volunteers were total-body exposed to 1-1 .…”

Section: Discussionsupporting

confidence: 94%

In contrast to their murine counterparts, normal human keratinocytes and human epidermoid cell lines A431 and HaCaT fail to express IL-10 mRNA and protein

Teunissen¹,

Koomen²,

Jansen

et al. 1997

Clinical and Experimental Immunology

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“…Melanoma might provide a favorable environment for the development of these T regs via IL-10 secreted by melanoma cells (34). It will thus be important to determine whether other types of tumors yield such tumor antigen-specific IL-10-secreting T regs.…”

Section: Discussionmentioning

confidence: 99%

Circulating tumor antigen-specific regulatory T cells in patients with metastatic melanoma

Vence

Palucka

Fay

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

162

122

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Although it is accepted that regulatory T cells (T regs) contribute to cancer progression, most studies in the field consider nonantigenspecific suppression. Here, we show the presence of tumor antigenspecific CD4 ؉ T regs in the blood of patients with metastatic melanoma. These CD4 ؉ T regs recognize a broad range of tumor antigens, including gp100 and TRP1 (melanoma tissue differentiation antigens), NY-ESO-1 (cancer/testis antigen) and survivin (inhibitor of apoptosis protein (IAP) family antigen). These tumor antigen-specific T regs proliferate in peripheral blood mononuclear cells (PBMC) cultures in response to specific 15-mer peptides, produce preferentially IL-10 and express high levels of FoxP3. They suppress autologous CD4 ؉ CD25 ؊ T cell responses in a cell contactdependent manner and thus share properties of both naturally occurring regulatory T cells and type 1 regulatory T cells. Such tumor antigen-specific T regs were not detected in healthy individuals. These tumor antigen-specific T regs might thus represent another target for immunotherapy of metastatic melanoma.M olecular identification of human cancer antigens in the last decade, for example MART-1/MelanA or NY-ESO-1, has ushered in a new era of antigen-specific cancer immunotherapy targeting these antigens. Despite promising data in animal models, the use of therapeutic cancer vaccines in humans has not yet lived up to its promises. The improved understandings of antigen presentation, and most specifically in dendritic cell (DC) biology, represent a new avenue for research in the field. Ex vivo-generated and antigen-loaded DCs have been used as vaccines to improve immunity in patients with cancer (1). We have vaccinated patients with metastatic melanoma with ex vivo-generated dendritic cells loaded with either HLA-A*0201-restricted peptides derived from melanoma-associated antigens (2) or killed allogeneic melanoma cells (3). Despite some remarkable clinical responses, the overall objective tumor regression rate remains low (1). Because insufficient antitumor immunity might be due to immunosuppression driven by regulatory T cells (T regs), we engaged in identifying such cells in our patient population.T regs are specialized in the control of responsiveness to self. They are composed of subsets with distinct ontogeny and functions. Naturally occurring CD4 ϩ CD25 high T regs are produced in the thymus (4), and express FoxP3, a transcriptional factor critical for their development and function (5, 6). Their depletion results in the development of autoimmune diseases in murine models (7,8). Conversely, their adoptive transfer inhibits the occurrence of autoimmune diseases in disease-prone mice (9). CD4 ϩ CD25 high T regs suppress the immune responses in a cell contact-dependent manner through mechanisms that remain to be identified (10). T regs are also generated in the periphery from nonregulatory T cells (11)(12)(13)(14)(15)(16). These include regulatory type 1 (Tr1) (12) and Th3 (11) cells, both of which preferentially secrete regulatory cytoki...

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“…The presence as well as the progression of cervical cancer is associated with increased serum levels of IL-10. 22 In addition to elevated host production of IL-10, some tumour cells produce significant amounts of this cytokine, 23,24 thus further increasing the local tissue concentration. It is unclear whether high IL-10 production is a precondition or a consequence of oncogenesis.…”

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confidence: 99%

Cancer of the uterine cervix may be significantly associated with a gene polymorphism coding for increased IL-10 production

et al. 2001

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The purpose of our prospective, case-controlled study was to investigate the hypothesis that women who are genetically programmed to produce high or medium levels of IL-10 were more likely to develop cancer of the uterine cervix than individuals genetically predisposed to low IL-10 production. The population was recruited from patients attending gynecological clinics at 2 hospitals in Harare, Zimbabwe. Laboratory tests were performed in the Departments of Immunology, Chemical Pathology and Medical Microbiology, Medical School, University of Zimbabwe, and simultaneously at the Department of Biological Sciences, University of Manchester, United Kingdom. Included in our study were 77 women with histologically proven cancer of the uterine cervix and 69 age-and parity-matched healthy women. All of the patients and healthy controls were from the Shona ethnic group that inhabits northern Zimbabwe. DNA was purified from cervical cytobrush samples obtained from women with cervical cancer. Control DNA was extracted from urine or peripheral blood samples from the healthy women. The Qiagen DNA extraction kit was used. Detection of allele A and/or G at ؊1082 in the promoter region of the IL-10 gene was carried out using the ARMS-PCR technique. Polymorphism in the amplified products was detected by gel electrophoresis in the presence of ethidium bromide and were bands visualized under UV light. The data comprise 77 women who developed invasive cervical cancer and 69 healthy women matched for age and parity. Patients with cancer were significantly (p ‫؍‬ 0.001) more likely to be predisposed to produce higher (A/G) levels of IL-10. The genotype encoding for high (G/G) production of IL-10 was only observed in one cancer patient. The prevalence of low producers of IL-10 in the cancer group was significantly lower than in the healthy women. There were no high producers amongst the healthy women. These data suggest that the genetically acquired ability to produce higher levels of IL-10 may be a significant factor in the development of cervical cancer.

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Expression of interleukin 10 in human melanoma

Cited by 127 publications

References 22 publications

In contrast to their murine counterparts, normal human keratinocytes and human epidermoid cell lines A431 and HaCaT fail to express IL-10 mRNA and protein

In contrast to their murine counterparts, normal human keratinocytes and human epidermoid cell lines A431 and HaCaT fail to express IL-10 mRNA and protein

Circulating tumor antigen-specific regulatory T cells in patients with metastatic melanoma

Cancer of the uterine cervix may be significantly associated with a gene polymorphism coding for increased IL-10 production

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