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IL-4 inhibits the TNF-α induced proliferation of renal cell carcinoma (RCC) and cooperates with TNF-α to induce apoptotic and cytokine responses by RCC: implications for antitumor immune responses

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Abstract

Objective: While previous reports clearly demonstrated antiproliferative effects of IL-4 on renal cell carcinoma (RCC) in vitro, the administration of IL-4 to patients with metastatic RCC in clinical trials could not recapitulate the promising preclinical results. In the present study we wanted to examine the context of IL-4 action and to establish conditions of enhanced IL-4 efficacy. Methods: Primary and permanent human RCC cells were cultured in either serum-supplemented or chemically defined, serum-free culture medium in the presence or absence of cytokines. Cell proliferation was assessed as [3H]-thymidine incorporation. Cell apoptosis was measured using the fluorescent DNA intercalator 7-aminoactinomycin D and flow cytometry. In addition, culture media conditioned by RCC were subjected to cytokine antibody array and cytokine multiplex analysis. Results: Our results indicate that the previously reported antiproliferative effects of IL-4 are serum-dependent. Under serum-free conditions, IL-4 failed to exhibit growth-inhibitory effects or was even growth-stimulatory. In a chemically defined, serum-free medium (AIM-V), however, IL-4 inhibited the TNF-α induced proliferation of RCC. IL-4 and TNF-α synergistically induced apoptosis of RCC as well as a complex cytokine response by RCC, which included the synergistic upregulation of RANTES and MCP-1. Conclusions: IL-4 alone has little effect on the spontaneous proliferation of RCC but can prevent the enhancement of proliferation induced by growth promoters like FBS and TNF-α. The concomitant growth inhibitory, apoptosis-inducing, and cytokine-enhancing effects of IL-4 in combination with TNF-α on RCC support the view that Th2 cytokines may be required for productive immune responses against RCC.

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Abbreviations

CCR:

Chemokine (C-C motif) receptor 3

CTL:

Cytotoxic T lymphocyte

ECL:

Enhanced chemoluminescence

ECM:

Extracellular matrix

EGF:

Epidermal growth factor

FACS:

Fluorescence activated cell sorting

FBS:

Fetal bovine serum

FGF:

Fibroblast growth factor

GDNF:

Glial cell derived neurotrophic factor

GRO:

Growth-related oncogene

HGF:

Hepatocyte growth factor

HRP:

Horse radish peroxidase

IFN:

Interferon

IL:

Interleukin

MAP:

MultiAnalyte profiling

MCP-1:

Monocyte chemoattractant protein

M-CSF:

Macrophage colony-stimulating factor

MHC:

Major histocompatibility complex

NAP:

Neutrophil activating protein

RANTES:

Regulated upon activation, normal T-cell expressed, and presumably secreted

RCC:

Renal cell carcinoma

Th:

T helper

TNF:

Tumor necrosis factor

TIMP:

Tissue inhibitor of metalloproteinase

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Acknowledgment

We thank the Tilak, the holding company of our hospital for continuous support. This work was supported by a grant of the kompetenzzentrum medizin tirol (kmt) awarded to M.T.

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Authors and Affiliations

  1. Department of Urology kompetenzzentrum medizin tirol (kmt), Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria

    Claudia Falkensammer, Hubert Gander, Reinhold Ramoner, Thomas Putz, Andrea Rahm, Georg Bartsch & Martin Thurnher

  2. Tyrolean Cancer Research Institute, Innrain 66, 6020, Innsbruck, Austria

    Karin Jöhrer & Richard Greil

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  1. Claudia Falkensammer
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Correspondence to Martin Thurnher.

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Falkensammer, C., Jöhrer, K., Gander, H. et al. IL-4 inhibits the TNF-α induced proliferation of renal cell carcinoma (RCC) and cooperates with TNF-α to induce apoptotic and cytokine responses by RCC: implications for antitumor immune responses. Cancer Immunol Immunother 55, 1228–1237 (2006). https://doi.org/10.1007/s00262-006-0122-1

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