Interleukin-18 inhibits lodging and subsequent growth of human multiple myeloma cells in the bone marrow

Abstract

An intravenous injection of ARH-77 cells (human multiple myeloma cell line) into mice with severe combined immunodeficiency disease (SCID mice) results in lodging of tumor cells in the bone marrow of thoracic and lumbar vertebrae, and in their subsequent growth, the cells destroying bone and invading the spinal cord and surrounding tissues, and the mice show hind leg paralysis. Using this model, we investigated the effects of interleukin (IL)-18 on the lodging and subsequent growth of multiple myeloma cells in the bone marrow. Mouse recombinant IL-18 (mIL-18) at 1 microg/mouse was daily injected according to protocols A and B. In protocol A, mIL-18 was injected from day 6 after tumor cell injection to examine the effect of mIL-18 on tumor growth, and in protocol B, it was injected from day 3 prior to tumor cell injection to day 3 after it to examine the effect of mIL-18 on lodging of tumor cells. The spread of a tumor was monitored as to the appearance of hind leg paralysis and the tumor area in a median longitudinal section of the vertebrae with the surrounding tissues. With protocol A, mIL-18 significantly and markedly decreased the cumulative rate of hind leg paralysis and the tumor area. This antitumor effect of mIL-18 was ascribed to its action on the activation of NK cells because mIL-18 exerted no significant effect when anti-asialo GM1 antiserum (a-ASGM1) was simultaneously injected to deplete the NK cell activity. With protocol B, mIL-18 also significantly and markedly decreased the cumulative rate of hind leg paralysis and the tumor area. However, most of this effect was not due to the action of mIL-18 on NK cells because mIL-18 showed a marked and significant effect with the administration of a-ASGM1. The present results indicate that mIL-18 inhibited the lodging and subsequent growth of multiple myeloma cells in the bone marrow, and suggest that IL-18 is worth investigating further as to its usefulness as a therapy for multiple myeloma.