ANTIPROLIFERATIVE EFFECT OF HUMAN INTERLEUKIN-4 IN HUMAN CANCER CELL-LINES - STUDIES ON THE MECHANISM

Interleukin-4 (IL-4) plays an important role in activating the immune system against malignant cells. The human interleukin-4 receptor (hIL- 4R) is not only expressed by hematopoietic cells but also on a large n umber of tissue specimens which include colon, breast and lung carcino mas. In this study we report that rhIL-4 has an antiproliferative effe ct on 2 out of 3 non-small cell lung carcinoma (NSCLC) cell lines in v itro as measured by human tumor cloning assays (HTCA). In comparison, rhIL-4 had no effect on the growth of small cell lung carcinoma cell l ines (SCLC) in vitro. The response towards the cytokine is correlated with expression of at least 1500 high affinity receptors/cell for hIL- 4 on the responsive cell lines. Xenotransplanting the human lung tumor cell lines into nude mice followed by 12 days of systemic treatment o f the mice with rhIL-4 revealed a significant growth retardation of th e IL-4R positive NSCLC cell lines when compared with the controls, whe reas the growth of the IL-4R negative SCLC cell lines was unaffected a lso in vivo. Studies of possible mechanisms involved in the antiprolif erative effect of rhIL-4 showed that rhIL-4 does not induce apoptosis or modulation of the transcription factor c-myc in the responsive NSCL C cell lines. Additionally, the expression of the epidermal growth fac tor receptor (EGFR), which is discussed as mediating autocrine/paracri ne growth stimulation of NSCLC, is unaffected by rhIL-4. However, we h ave observed that rhIL-4 inhibited G(1)-S-phase cell cycle progression . We conclude that rhIL-4 has an antiproliferative effect on the growt h of some NSCLC in vitro and in vivo. The mechanisms involved remain t o be further elucidated.