Lattanzio, G. et al. Defective development of pristane-oil-induced plasmacytomas in interleukin-6-deficient BALB/c mice. Am. J. Pathol. 151, 689-696

Dipartimento di Patologia Umana e Medicina Sociale, Università di Chieti, Italy.
American Journal Of Pathology (Impact Factor: 4.59). 10/1997; 151(3):689-96.
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Interleukin (IL)-6 is known to be an essential growth factor for myeloma cells, both in vitro and in vivo. In mice, IL-6 is required for development of B cell tumors upon infection with a retrovirus expressing the myc/raf oncogenes. In the present study, we used the pristane-oil-induced plasmacytoma model, which more closely mimics tumor transformation and progression in human multiple myeloma. Also using this system, we found that IL-6-deficient BALB/c mice are protected against tumor development. Although the pristane-induced inflammatory reaction was less pronounced in IL-6-deficient mice versus their wild-type littermates, both B cell differentiation and plasma cell formation took place, and even morphological evidence of plasma cell transformation was detected, albeit at a low frequency. However, in the absence of IL-6, there were never signs of uncontrolled proliferation of either normal B lymphocytes or tumor cells, suggesting that the role of IL-6 in murine plasmacytoma and possibly also in human multiple myeloma is to ensure abnormal survival and proliferation of previously transformed tumor cells and therefore tumor development and progression.

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    • "BALB/c mice develop murine plasmacytoma (MPC) upon intraperitoneal administration of pristane, (2,6,10,14-tetram- ethylpentadecane), a component of mineral oil [1] [2] [3] [4] [5]. IL-6, TGF-í µí»½1, and other factors are required for transformation of B lymphocyte to MPC [6] [7] [8]. IL-6 blocks the differentiation of the Treg cells [9] [10] which inhibit autoreactive T cell and modulate immune functions by releasing TGF-í µí»½1 and IL-10 [11], but it promotes the generation of proinflammatory Th17 cells, characterized by the expression of ROR í µí»¾t transcription factor and the production of IL-17, which induces the production of a wide range of proinflammatory cytokines and neutrophil-attracting chemokines [12]. "
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    ABSTRACT: BALB/c strain mice are unique in that they develop murine plasmacytoma (MPC) as a consequence of the inflammation induced by pristane oil injection in the peritoneal cavity. In this work the Treg, Th17, B1, B2, and NHC lymphocyte populations from the peritoneal environment of BALB/c, the susceptible strain, and C57BL/6 mice, which do not develop MPC after oil treatment, were studied. Both oil-treated strains showed decreased levels of Th17 lymphocytes, no significant variation in Treg lymphocytes, and a drastic decrease of all B lymphocyte populations. However, only oil-induced BALB/c showed increased levels of natural helper cells (NHC) which could be important in the myeloma induction.
    Mediators of Inflammation 01/2015; 2015(9):1-9. DOI:10.1155/2015/313140 · 3.24 Impact Factor
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    • "Cytokines released by bone marrow stromal cells (BMSCs) and/or MM cells that have been described to have this supportive potential include interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), insulin-like growth factor-1, basic fibroblast growth factor, IL-1, IL-10, IL-11, IL-15, IL-21, granulocyte macrophage colony-stimulation factor (GM-CSF), interferon-α, and leukemia inhibitory factor [3]. Among these cytokines, IL-6 has been most widely studied and is considered to play a pivotal role as a growth and survival factor for myeloma cells [4] [5] [6] [7]. Evidence indicates that elevated IL-6 expression in the tumor microenvironment may be a major factor leading to drug resistance [8] [9] [10]. "
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    ABSTRACT: Cytokines in the bone marrow of multiple myeloma patients activate Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathways in tumor cells and promote tumor growth, survival, and drug resistance. INCB16562 was developed as a novel, selective, and orally bioavailable small-molecule inhibitor of JAK1 and JAK2 markedly selective over JAK3. The specific cellular activity of the inhibitor was demonstrated by its potent and dose-dependent inhibition of cytokine-dependent JAK/STAT signaling and cell proliferation in the absence of effects on Bcr-Abl-expressing cells. Treatment of myeloma cells with INCB16562 potently inhibited interleukin-6 (IL-6)-induced phosphorylation of STAT3. Moreover, the proliferation and survival of myeloma cells dependent on IL-6 for growth, as well as the IL-6-induced growth of primary bone marrow-derived plasma cells from a multiple myeloma patient, were inhibited by INCB16562. Induction of caspase activation and apoptosis was observed and attributed, at least in part, to the suppression of Mcl-1 expression. Importantly, INCB16562 abrogated the protective effects of recombinant cytokines or bone marrow stromal cells and sensitized myeloma cells to cell death by exposure to dexamethasone, melphalan, or bortezomib. Oral administration of INCB16562 antagonized the growth of myeloma xenografts in mice and enhanced the antitumor activity of relevant agents in combination studies. Taken together, these data suggest that INCB16562 is a potent JAK1/2 inhibitor and that mitigation of JAK/STAT signaling by targeting JAK1 and JAK2 will be beneficial in the treatment of myeloma patients, particularly in combination with other agents.
    Neoplasia (New York, N.Y.) 01/2010; 12(1):28-38. DOI:10.1593/neo.91192 · 4.25 Impact Factor
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    • "The resulting heterozygous offspring were bred together to generate homozygous mice (IL−/−) for the mutation. These procedures have been described in greater detail [27] [34]. Wild type (WT) littermates (IL-6+/+) were used as controls. "
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    ABSTRACT: Interleukin-6 (IL-6) is a cytokine shown to affect brain function and to be involved in pathological neurodegenerative disorders such as Alzheimer's disease (AD). In the present study we investigated the cognitive function in transgenic mice not expressing IL-6 (IL-6 KO) and in wild type (WT) genotype at 4 and 12 months of age, using a passive avoidance and an eight-arm radial maze tasks. Motor function was quantified using an Animex apparatus. Hippocampal choline acetyltransferase (ChAT) activity was evaluated in both genotypes. No difference was observed in both genotypes for spontaneous motor activity. The mean latency (s) to re-enter the shock box, was similar in both young mutant and WT mice. However, a decreased sensitivity (50%) to scopolamine (1 mg/kg) in mutant compared to WT mice, was obtained. IL-6 KO mice exhibited a facilitation of radial maze learning over 30 days, in terms of a lower number of working memory errors and a higher percentage of animals reaching the criterion as compared with WT genotype tested at both ages. Furthermore, mutant mice, at the age of 12 months, showed a faster acquisition (22 days versus 30 days to reach the criterion). The pattern of arm entry exhibited by IL-6 KO mice showed a robust tendency to enter an adjacent arm at both ages, while WT only at the age of 4 months. ChAT activity was inversely correlated with memory performance. These findings suggest a possible involvement of IL-6 on memory processes, even if the mechanism remains still unclear.
    Behavioural Brain Research 09/2004; 153(2):423-9. DOI:10.1016/j.bbr.2003.12.018 · 3.03 Impact Factor
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