Rapid recruitment of macrophages in interleukin-12-mediated tumour regression

Immunology. 1998 Sep;95(1):156-63. doi: 10.1046/j.1365-2567.1998.00579.x.


In order to study the mechanism of interleukin-12 (IL-12) antitumour activity, RH7777 rat hepatoma cells were engineered to express mouse IL-12 (mIL-12) (RH7777/mIL-12) under the tight control of doxycycline (dox). The production of the mIL-12 protein was regulated by the concentration of dox that was present in the culture medium. RH7777/mIL-12 cells appeared to have the same tumorigenic activity as did parental RH7777 cells, when subcutaneously injected into syngeneic rat (BUF/N) in the absence of dox. However, the tumorigenicity of RH7777/mIL-12, but not RH7777, cells were significantly decreased when dox was administrated to the animals. In addition, established tumours of RH7777/mIL-12 cells gradually disappeared upon the induction of mIL-12 by dox. To elucidate the kinetic profile of immune cells involved in the mIL-12-induced tumour regression, both histological and immunohistochemical analyses were performed 1, 3 and 14 days after the dox treatment on rats bearing tumours that were approximately 0. 5 cm in diameter. Tumour-infiltrating macrophages began to appear at the tumour site one day after dox treatment. As time elapsed, the number of tumour infiltrates including CD4+, CD8+, natural killer (NK) cells and macrophages gradually increased. In particular, CD8+ and NK cells constituted the major population of the tumour-infiltrated cells. Furthermore, it was found that resting peritoneal macrophages (PM) from rats were chemoattracted in response to mIL-12. The effects of mIL-12 on PM chemotaxis were reproducibly observed in concentrations as low as 0.1 ng/ml. These findings suggest that IL-12 can directly recruit macrophages into tumour sites which, in turn, leads to a broad and intense immunological response against tumour.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / therapeutic use
  • Antibodies, Monoclonal / therapeutic use
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Chemotactic Factors / therapeutic use*
  • Doxycycline / therapeutic use
  • Gene Transfer Techniques
  • Histocytochemistry
  • Immunohistochemistry
  • Interleukin-12 / genetics
  • Interleukin-12 / therapeutic use*
  • Killer Cells, Natural / immunology
  • Liver Neoplasms, Experimental / immunology
  • Liver Neoplasms, Experimental / therapy*
  • Macrophages, Peritoneal / drug effects*
  • Mice
  • Neoplasm Transplantation
  • Rats
  • Rats, Inbred BUF
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / immunology*


  • Anti-Bacterial Agents
  • Antibodies, Monoclonal
  • Chemotactic Factors
  • Interleukin-12
  • Doxycycline