Serum Levels of Cytokines and Soluble Cytokine Receptors in Patients with Metastatic Renal Cell Carcinoma or Malignant Melanoma Receiving IL-2/Interferon-α Combination Therapy

Fosså, Sophie D.; Aamdal, S.; Naume, Bjørn; Gallati, H.

doi:10.3109/02841869509094034

Cited by 15 publications

(7 citation statements)

References 20 publications

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“…(11) Several reports have noted that IL-10 is produced by a variety of tumor cells. (9,(12)(13)(14)(15) For example, elevated IL-10 mRNA levels were found in human ovarian carcinoma, skin cancers, (16,17) lymphoma, (18,19) neuroblastoma, renal cancer, colon carcinoma, (15) and non-small cell lung cancer. (20) Furthermore, the levels of IL-10 mRNA and protein are elevated in malignant melanoma cells compared with normal melanocytes.…”

Section: Introductionmentioning

confidence: 99%

Increased Interleukin-10 mRNA Stability in Melanoma Cells Is Associated with Decreased Levels of A + U-Rich Element Binding Factor AUF1

Brewer

Saccani²,

Sarkar³

et al. 2003

Journal of Interferon & Cytokine Research

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Abnormal production of interleukin-10 (IL-10) is observed in some pathologic conditions. For example, compared with normal melanocytes, IL-10 expression is elevated in melanoma cells. IL-10 overexpression could inhibit both immune surveillance and tumor rejection. We investigated a potential posttranscriptional mechanism for IL-10 overexpression in melanoma cells. In normal melanocytes, the half-life of IL-10 mRNA is 7 min, whereas in the melanoma cell line MNT1, the half-life is 75 min. This 10-fold difference could account, at least in part, for IL-10 overexpression in MNT1 cells. Examination of the 3'-untranslated region (3'-UTR) of IL-10 mRNA revealed a suspected A + U-rich element (ARE) that might target the mRNA for rapid degradation. Transfection experiments confirmed that these sequences promote rapid degradation when inserted into a normally stable mRNA, indicating ARE functionality. As AREs act via their interactions with ARE-binding proteins, we examined cytoplasmic proteins from normal melanocytes and MNT1 cells for IL-10 ARE-binding activity. Compared with cytoplasmic extracts of normal melanocytes, cytoplasmic extracts of MNT1 cells possess substantially less ARE-binding activity, consistent with the extended half-life of IL-10 mRNA in MNT1 cells. Finally, we find that the ARE-binding protein AUF1 comprises the major ARE-binding activity in cytoplasmic extracts of normal melanocytes. By contrast, AUF1 is not detectable in cytoplasmic extracts of MNT1 cells but appears restricted to the nuclear fraction. Together, these data suggest a mechanism whereby reduced cytoplasmic levels of AUF1 in MNT1 melanoma cells may lead to IL-10 overexpression, with deleterious consequences for tumor surveillance and rejection.

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Section: Introductionmentioning

confidence: 99%

Increased Interleukin-10 mRNA Stability in Melanoma Cells Is Associated with Decreased Levels of A + U-Rich Element Binding Factor AUF1

Brewer

Saccani²,

Sarkar³

et al. 2003

Journal of Interferon & Cytokine Research

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“…In addition, its expression is elevated in patients with a variety of peripheral blood or bone marrow-derived leukemias, certain B cell and T cell lymphomas and nasal natural killer cell lymphomas and other hematopoietic and solid tumors (1)(2)(3)(4)(5). Two mechanisms of IL-10 action can be used by tumors.…”

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confidence: 99%

Human cytomegalovirus harbors its own unique IL-10 homolog (cmvIL-10)

Kotenko¹,

Saccani²,

Izotova³

et al. 2000

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

442

365

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We identified a viral IL-10 homolog encoded by an ORF (UL111a) within the human cytomegalovirus (CMV) genome, which we designated cmvIL-10. cmvIL-10 can bind to the human IL-10 receptor and can compete with human IL-10 for binding sites, despite the fact that these two proteins are only 27% identical. cmvIL-10 requires both subunits of the IL-10 receptor complex to induce signal transduction events and biological activities. The structure of the cmvIL-10 gene is unique by itself. The gene retained two of four introns of the IL-10 gene, but the length of the introns was reduced. We demonstrated that cmvIL-10 is expressed in CMVinfected cells. Thus, expression of cmvIL-10 extends the range of counter measures developed by CMV to circumvent detection and destruction by the host immune system. I L-10 is a pleiotropic immunomodulatory cytokine produced by CD4 ϩ and CD8 ϩ T cells, monocytes͞macrophages, keratinocytes, and activated B cells (1). In addition, its expression is elevated in patients with a variety of peripheral blood or bone marrow-derived leukemias, certain B cell and T cell lymphomas and nasal natural killer cell lymphomas and other hematopoietic and solid tumors (1-5). Two mechanisms of IL-10 action can be used by tumors. IL-10 appears to act as an autocrine growth factor for B cell lymphomas. In addition, IL-10 selectively inhibits certain aspects of the cellular immune response. It blocks proinflammatory cytokine synthesis and suppresses the ability of macrophages to serve as antigen-presenting or costimulatory cells (6-8). Thus, IL-10 is a powerful anti-inflammatory agent and a potent immunosuppressor.Many viruses exploit the strategy of using homologs of cellular cytokines or cytokine receptors to shield virus-infected cells from immune defenses and enhance virus survival in the host. The presence of virus-encoded homologs of cellular proteins may be an indicator of the importance of these cellular components in immune mechanisms for combating this virus in vivo. A number of herpes viruses harbor homologs of IL-10. Epstein-Barr virus (EBV)-encoded IL-10 (ebvIL-10), the first viral homolog of IL-10 identified (9, 10), shares many but not all of the biological activities of cellular IL-10 and may play an important role in the host-virus interaction (1,11,12). In addition to EBV, another virus, the Orf poxvirus (OV), which can infect humans, has its own IL-10 homolog, ovIL-10 (13). Whether it is active on human cells remains to be shown. The exact in vivo roles of viral IL-10 homologs in the viral life cycle, in immune evasion, and͞or in helping virus-infected cells to survive immune surveillance remain to be defined.Human cytomegalovirus (CMV) is a widespread herpes virus that is able to persist for decades in its host. CMV is the major cause of a variety of life-threatening diseases in immunocompromised individuals, including transplant and AIDS patients, and is a leading cause of congenital birth defects (14). CMV is also associated with the development of atherosclerosis, restenosis after coronary...

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“…The documented immune reaction against RCC [ 5] has provoked the development of new immunotherapeutic strategies. The effect of systemic applications of IFN‐α for the general stimulation of the immune system has been investigated [ 15]; 10 (21%) of patients showed a positive response to this therapy, although there was no evidence of an increase in survival time [ 7, 9, 21]. Interleukin‐2 has also produced an objective response in a third of patients with advanced RCC, although even the combination of both agents resulted in a long‐term benefit in only 4–6% of the patients [ 7, 9].…”

Section: Discussionmentioning

confidence: 99%

Autologous and allogenic hybrid cell vaccine in patients with metastatic renal cell carcinoma

Kugler¹,

Seseke²,

Thelen³

et al. 1998

British Journal of Urology

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Objective To evaluate the safety, acute and long‐term toxicity and therapeutic activity of an allogenic and an autologous hybrid cell vaccine in patients with progressive metastatic renal cell carcinoma (RCC). Patients and methods Eleven patients were vaccinated with a lethally irradiated hybrid cell vaccine of allogenic RCC tumour cells fused with major histocompatibility complex class I‐matched and class II‐unmatched activated allogenic lymphocytes. These patients were then followed for a mean of 11 months. Another 13 patients were vaccinated with a hybrid cell vaccine of autologous tumour cells fused with allogenic activated lymphocytes and followed for a mean of 6 months. Results Six of the 11 patients receiving the allogenic vaccination showed an initial response, with two complete and two partial responses to date. Only three patients who received autologous vaccination responded to treatment. Conclusions Hybrid cell vaccination is a promising new approach in the treatment of patients with advanced RCC.

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Serum Levels of Cytokines and Soluble Cytokine Receptors in Patients with Metastatic Renal Cell Carcinoma or Malignant Melanoma Receiving IL-2/Interferon-α Combination Therapy

Cited by 15 publications

References 20 publications

Increased Interleukin-10 mRNA Stability in Melanoma Cells Is Associated with Decreased Levels of A + U-Rich Element Binding Factor AUF1

Increased Interleukin-10 mRNA Stability in Melanoma Cells Is Associated with Decreased Levels of A + U-Rich Element Binding Factor AUF1

Human cytomegalovirus harbors its own unique IL-10 homolog (cmvIL-10)

Autologous and allogenic hybrid cell vaccine in patients with metastatic renal cell carcinoma

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