Rapid recruitment of macrophages in interleukin-12-mediated tumour regression.
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.
Ha
S J
SJ
Department of Life Science, Pohang University of Science and Technology, Center for Biofunctional Molecules, Pohang, Kyungbuk, South Korea.
Lee
S B
SB
Kim
C M
CM
Shin
H S
HS
Sung
Y C
YC
D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002630:Chemotactic Factors / Q000627:therapeutic use*; D004318:Doxycycline / Q000627:therapeutic use; D018014:Gene Transfer Techniques; D006651:Histocytochemistry; D007150:Immunohistochemistry; D018664:Interleukin-12 / Q000235:genetics / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000276:immunology; D008114:Liver Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D017737:Macrophages, Peritoneal / Q000187:drug effects*; D051379:Mice; D009368:Neoplasm Transplantation; D051381:Rats; D011915:Rats, Inbred BUF; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000276:immunology*
D000900:Anti-Bacterial Agents; D000911:Antibodies, Monoclonal; D002630:Chemotactic Factors; D018664:Interleukin-12; D004318:Doxycycline