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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Apoptosis / immunology
  • Carcinoma, Renal Cell / immunology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Cytokines / drug effects
  • Cytokines / immunology
  • Flow Cytometry
  • Humans
  • Interleukin-4 / immunology
  • Interleukin-4 / pharmacology*
  • Kidney Neoplasms / immunology*
  • Tumor Necrosis Factor-alpha / immunology*


  • Cytokines
  • Tumor Necrosis Factor-alpha
  • Interleukin-4