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Flavone Acetic Acid Directly Induces Expression of Cytokine Genes in Mouse Splenic Leukocytes but not in Human Peripheral Blood Leukocytes¹

Laboratory of Experimental Immunology, Biological Response Modifiers Program, Division of Cancer Treatment [H. F., M. E. G., J. R. O., H. A. Y., R. H. W.], and Biological Carcinogenesis and Development Program, PRI/DynCorp. [L. A. E., K. L. K., R. B.], National Cancer Institute-Frederick Cancer Research and Development Center (NCI-FCRDC), Frederick, Maryland 21702-1201

Flavone-8-acetic acid (FAA) is a flavonoid drug that augments mouse natural killer activity, induces cytokine gene expression, and synergizes with recombinant interleukin 2 for the treatment of murine renal cancer. However, FAA has been largely inactive in human clinical trials. In the present study we investigated the ability of FAA treatment to directly induce cytokine mRNA expression in total mouse splenic leukocytes and selected leukocyte subsets, as well as in total human peripheral blood leukocytes. Analysis of RNA isolated from FAA-treated mouse splenic leukocytes demonstrated that treatment with 100 µg/ml of FAA induced expression of tumor necrosis factor (TNF-) mRNA by 1 h and induced maximal expression of TNF-, -interferon, and -interferon mRNA within 3 h. The expression of all cytokine genes was diminished by 6 h. Interferon biological activity was detected in the supernatants of mouse splenic or peripheral blood leukocytes after treatment with FAA. These results correlate well with the previously reported induction of cytokine mRNA genes and biological activity by FAA in vivo. In contrast, FAA did not induce detectable mRNA expression or cytokine protein secretion by human peripheral blood leukocytes under similar conditions. These results demonstrate that FAA can directly stimulate cytokine gene expression in mouse but not in human leukocytes. Further studies performed with highly purified positively selected mouse CD4⁺ or CD8⁺ splenic T-lymphocytes, as well as purified B-cells, demonstrated that the FAA-induced expression of -interferon mRNA was mainly induced in the CD8⁺ lymphocyte subset. -Interferon mRNA was expressed largely in the B-cell population, while TNF- mRNA was induced in all leukocyte subsets tested. Therefore, these results suggest that the immunomodulatory effects of FAA in mice are direct, but different cytokines are induced from different leukocyte subsets. Further, the data suggest that flavonoid compounds or analogues that stimulate cytokine gene expression in human cells might be therapeutically active in cancer patients.

¹ This project has been funded at least in part with federal funds from the Department of Health and Human Services under Contract NO1-CO-74102 with Program Resources, Inc./DynCorp.

² Recipient of support during the performance of these studies from a Japanese Overseas Cancer Research Fellowship from the Foundation for the Promotion of Cancer Research. Present address: Growth Factor Division, National Cancer Center Research Institute, Tsukiji 5-1-1, Cho-Ku, Tokyo 104, Japan.

³ To whom requests for reprints should be addressed, at the Laboratory of Experimental Immunology, NCI-FCRDC Bldg. 560, Rm. 31-93, Frederick, MD 21702-1201.

Received 7/15/91. Accepted 10/ 3/91.

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