Gp130 and ras mediated signaling in human plasma cell line INA-6: a cytokine-regulated tumor model for plasmacytoma.

INTRODUCTION: Cytokines of the gp130-family, particularly interleukin(IL)-6, play a crucial role in the propagation of malignant plasma cells. MATERIALS AND METHODS: The role of IL-6 and other gp130-cytokines was studied in the human plasma cell line INA-6 in vitro and in INA-6 xenografts. The proliferative response to gp130-cytokines was evaluated and activated components of gp130-signaling pathways were identified by Western blotting and DNA binding studies. Specifically, expression of IL-6 and receptors for IL-6 and leukemia inhibitory factor were analysed by RT-PCR and ELISA. RESULTS: The plasma cell line INA-6 was cultured for several years remaining strictly dependent on exogenous IL-6. Other gp130-cytokines had no significant effect on INA-6 cell proliferation in vitro. Due to an activating mutation in the N-ras gene, mitogen-activated protein kinases (MAPK) were constitutively phosphorylated. In contrast, signal transducer and activator of transcription(STAT)-3 activation was dependent on stimulation with IL-6. Blocking of either one of these pathways resulted in a significant decrease of INA-6 cell proliferation. Remarkably, INA-6 xenografts did not require exogeneous IL-6 for proliferation in vivo. Instead, an autocrine IL-6 loop and, in certain tumor sublines, responsiveness to additional gp130-cytokines was induced during in vivo growth. CONCLUSION: Activation of the gp130 signal transducer is mandatory for INA-6 cell growth in vitro and in vivo. Both the MAPK and the Jak/STAT pathway are operative in malignant plasma cells and either one is essential for plasma cell growth. The INA-6 cell line provides a preclinical model to study growth regulation of human plasmacytoma cells and to evaluate novel therapeutic strategies.

Multifocal fixed drug eruption to paracetamol, tropisetron and ondansetron induced by interleukin 2.

Fixed drug eruptions (FDEs) represent an uncommon subset of drug reactions where typically dusky red skin eruptions recur at the same site each time a drug is administered. Multifocal FDEs are defined by skin eruptions at more than one site. We describe a patient with metastatic melanoma who developed a multifocal FDE to paracetamol, tropisetron and ondansetron during chemoimmunotherapy with interleukin 2 (IL-2) and dacarbazine. This case is unique since to our knowledge there has been no previous report of such a drug reaction to tropisetron. Moreover, recurrences were induced by drugs which were chemically unrelated (i.e. tropisetron and paracetamol). We propose that this unusual skin reaction to multiple drugs was induced by IL-2 administered during immunochemotherapy for the metastatic melanoma.