Mouse plasmacytoma growth in vivo: enhancement by interleukin 6 (IL-6) and inhibition by antibodies directed against IL-6 or its receptor.

Abstract

SummaryMurine plasmacytomas show a striking dependence on interleukin 6 (IL6) for their growth in vitro. Here, we present evidence suggesting that IL6 also plays an essential role in the in vivo development of these tumors . This conclusion is based on the finding that the tumorigenicity of an IL-6-dependent plasmacytoma cell line was increased -100-fold on transfection with an IL-6 expression vector, whereas it was inhibited in animals treated with monoclonal antibodies capable of blocking the binding of IL6 to its receptor. Injection of these antibodies 1 d before tumor challenge protected >50% ofthe mice and retarded tumor growth in all animals . Tumors arising in antibody-treated mice retained their 11,6 dependence in vitro, suggesting that the level of protection could be improved if stronger IL6 antagonists were available. I t is now well established that IL6 is a critical factor for the in vitro growth and survival of mouse plasmacytomas (1, 2), and there is increasing support for the idea that it plays an important role in the in vitro proliferation of human myelomas as well (3-6) . The notion that IL-6 may also be of importance for the in vivo growth of these tumors is supported by the following observations: (a) pristane-induced granulomas, which produce large amounts of IL6 (1), are critical not only for induction (7) but also for early transplantation of mouse plasmacytomas (8) ; (b) overexpression of IL6 in transgenic mice, although not sufficient to cause the development of plasma cell tumors, induces strong plasmacytosis (9) ; and (c) transfection with IL6 cDNA was recently shown to increase the tumorigenicity of an 11,6-dependent B cell hybridoma (10). While none ofthese findings formally proves that IL6 is required for the in vivo growth of plasmarytomas, they clearly call for a direct evaluation of this possibility.In the present report, we addressed this question by examining whether the tumorigenicity of a mouse plasmacytoma could be increased by transfection with an IL6 cDNA and, more importantly, whether it could be inhibited by administration ofantibodies directed against IL6 or against its receptor.Plasmid Construction. A mouse 11,6 cDNA fragment of 827 by was isolated from clone pHP1B5 (11) by digestion with EcoRI and DraI. This fragment, which contains the entire coding sequence of11,6 but lacks -250 by at the 3' end of the gene, was subdoned into the Sall site of plasmid pBMGneo (12). Northern blot analysis was performed as described (11) using 32P-labeled mIL6 cDNA.Transfection ofPlasmacytoma Cells with 11,6 cDNA . ' IL6-dependent T1033C2 plasmacytoma cells were transfected by, electroporation, and transfectants containing the IIr6 expression vector were selected in G418. This population, terrkred TB6D2, secreted IL6 (-500 pg/106 cells/24 h, as measured; in the 7TD1 assay), and could be cloned in the absence of exogenous IL6 . A clone designated TB6D2 .M was selected for further study. A control group ofcells was transfected with the same plasmid containing the IL6 cDNA cloned in miss...

Interleukin-6 antisense oligonucleotides inhibit the growth of human myeloma cell lines.

“…For instance, transfection of the human IL-6 gene in murine plasmacytoma or hybridoma led to increased tumorigenicity (21,22). On the other hand, IL-6 gene transgenic mice exhibit a striking plasmacytosis but no transplantable plasma cell tumor could be obtained (23).…”

IL-6 and MYC collaborate in plasma cell tumor formation in mice

“…27 Critical evidence for the involvement of IL-6 in inflammation-induced peritoneal plasmacytomagenesis was first obtained in studies with C mice, showing that tumor growth is enhanced by exogenous IL-6 but inhibited by antibodies to IL-6 or its receptor. 28 Subsequent work demonstrated that C mice homozygous for a null allele of Il6 are resistant to both pristane-induced peritoneal PCT 29 and peritoneal PCT accelerated by a Myc/Raf retrovirus. 30 Conversely, C mice carrying the H2-L d -IL6 TG develop PCT spontaneously without a requirement for peritoneal inflammation.…”

Fiber-Modified Adenovirus Vectors Decrease Liver Toxicity through Reduced IL-6 Production

“…The IL-6 receptor system consists of two functional molecules, an 80-kDa ligand-binding chain (IL-6R) and a 130-kDa nonligand-binding but signal-transducing chain (gp130). The anti-IL-6R Ab blocks the binding of IL-6 to the IL-6R (38,39). The anti-IL-6R Ab or the control Ab was i.p.…”