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. 2006 Oct;55(10):1228-37.
doi: 10.1007/s00262-006-0122-1. Epub 2006 Jan 28.

IL-4 Inhibits the TNF-alpha Induced Proliferation of Renal Cell Carcinoma (RCC) and Cooperates With TNF-alpha to Induce Apoptotic and Cytokine Responses by RCC: Implications for Antitumor Immune Responses

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IL-4 Inhibits the TNF-alpha Induced Proliferation of Renal Cell Carcinoma (RCC) and Cooperates With TNF-alpha to Induce Apoptotic and Cytokine Responses by RCC: Implications for Antitumor Immune Responses

Claudia Falkensammer et al. Cancer Immunol Immunother. .

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 [(3)H]-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-alpha induced proliferation of RCC. IL-4 and TNF-alpha 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-alpha. The concomitant growth inhibitory, apoptosis-inducing, and cytokine-enhancing effects of IL-4 in combination with TNF-alpha on RCC support the view that Th2 cytokines may be required for productive immune responses against RCC.

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