IL-6-stimulated myeloma cell proliferation: Evidence for induction of autocrine IGF-I expression

Interleukin-6 (IL-6) has been identified as a potent growth factor for malignant plasma calls isolated from patients with aggressive multiple myeloma. By contrast, although IL-6 promotes the differentiation of normal B cells into plasma cells, it does not support their growth. We have recently shown that insulin-like growth factor (IGF) -I and -II may also play a key role in regulating myeloma cell growth. During the course of these studies, we made the preliminary observation that an IQF-I receptor- specific antibody, α-IR3, inhibited IL-6-stimulated myeloma cell growth. The focus of the present studies, therefore, was to define the mechanism by which this mAb inhibited IL-6 responsiveness. In our initial studies, we have assessed the effects of α-IR3 on IL-6-stimulated myeloma cell DNA synthesis when cells were cultured under IGF-free conditions. Of interest, treatment of myeloma cells with α-IR3 resulted in at least a fivefold reduction in IL-6 induced growth in the ANBL-6 and KAS-6/1 myeloma cell lines. To determine whether myeloma cells could express IGF-I or -II, we next isolated total RNA from myeloma cells maintained with IL-6 and used RT-PCR to detect the presence of IGF-I or -II transcripts. This analysis revealed that myeloma cells express IGF-I, but not IGF-II mRNA. RT-PCR was next used to determine If IL-6 modulated autocrine IGF-I expression. The KAS-6/1 cell line was cultured ± IL-6 for 20 hours prior to RNA harvest and RT-PCR to determine IGF-I mRNA levels. These results demonstrated that IL-6 stimulation increased IGF-I expression. In summary, our results suggest that IL-6 induces myeloma cell autocrine IGF-I expression. Because of the ability of the IGFs to enhance IL-6-stimulated growth, this may represent an important in vivo mechanism by which tumor cell growth is enhanced.