In the search for a more effective adjuvant therapy to treat multiple myeloma (MM), we investigated the effects of the traditional Chinese herbal medicines Huang-Lian-Jie-Du- Tang IntroductionMultiple myeloma (MM) is an incurable plasma-cell malignancy and the second most common hematologic malignancy, with 14 000 new patients diagnosed in the United States annually. 1,2 Although combination chemotherapy offers initial response rates of 40% to 70% in MM patients, 3 refractoriness to these regimens eventually develops. High-dose chemotherapy with stem cell support has achieved higher response rates than conventional therapy, but few patients remain in long-term remission. 4 Thus, the development of a more effective therapy to treat early and advanced MM has become a priority.Many components from herbs have been identified as effective in the treatment of human disease. Curcumin, a major component of turmeric, is able to correct defects associated with the homozygous expression of delta F508 cystic fibrosis 5 and to suppress the growth of myeloma cells. 6 Arsenic trioxide, a compound of arsenic, is very effective in the treatment of patients with acute promyelocytic leukemia who have developed resistance to all-trans retinoic acid (ATRA). 7 Artemisinins, extracted from sweet wormwood, are the most potent antimalarials available, rapidly killing Plasmodium falciparum at all asexual stages by inhibiting the sarcoplasmic or endoplasmic reticulum calcium ATPase (SERCA) ortholog (PfATP6) in Xenopus oocytes with a similar potency to thapsigargin. 8 Consequently, they are widely used to treat multidrug-resistant malaria, a disease that claims 1 million lives annually. 9 Inflammation and MM may be induced partly in the same way, as interleukin 6 (IL-6) is a potential mediator in these conditions. 10,11 Many Kampo medicines have been used historically in anti-inflammatory therapy. By screening the effects of antiinflammatory Kampo formulas on MM cells, we hoped to find one to treat MM. Huang-Lian-Jie-Du-Tang (HLJDT) contains Coptis rhizoma, Phellodendron bark, Scutellaria radix (root), and Gardenia fruit in 2.0, 1.5, 3.0, and 2.0 parts, respectively. It is recognized in Japan and China as an effective anti-inflammatory agent and has been widely used in the treatment of various inflammatory diseases such as gastritis, dermatitis, aphthous stomatitis, and hypertension. HLJDT exhibited anti-inflammatory activity in experimental colitis induced by dextran sulfate sodium, 12 and in animal experiments it inhibited the proliferation of lymphocytes under inflammatory conditions by suppressing the secretion of proinflammatory cytokines including interferon ␣ (IFN-␣) and IFN-␥. 13 The secretion of these cytokines was also reported to be suppressed by HLJDT in is the recipient of a Postdoctoral Fellowship Award for Foreign Researchers (P04500) from the Japan Society for the Promotion of Science (JSPS).Reprints: Michio M. Kawano, Department of Bio-Signal Analysis, AMES, Graduate School of Medicine, Yamaguchi University, 1-1-1 Minami-...
Specific intracellular signals mediated by interleukin-6 (IL-6) receptor complexes, such as signal transducer and activator of transcription 3 (STAT 3) and extracellu-lar signal-regulated kinase (ERK) 1/2, are considered to be responsible for inducing a variety of cellular responses. In multiple myeloma, IL-6 only enhanced the proliferation of CD45 tumor cells that harbored the IL-6-independent activation of src family kinases even though STAT3 and ERK1/2 could be activated in response to IL-6 in both CD45 and CD45 cells. Furthermore, the IL-6-induced proliferation of CD45 U266 myeloma cells was significantly suppressed by Lyn-specific antisense oligodeoxynucleo-tides or a selective src kinase inhibitor. These results indicate that the activation of both STAT3 and ERK1/2 is not enough for IL-6-induced proliferation of myeloma cell lines that require src family kinase activation independent of IL-6 stimulation. Thus, the activation of the src family kinases associated with CD45 expression is a prerequisite for the proliferation of myeloma cell lines by IL-6. We propose a mechanism for IL-6-induced cell proliferation that is strictly dependent upon the cellular context in myelomas. (Blood. 2002;99:2172-2178)
Interleukin-6 (IL-6) is a growth and antiapoptotic factor for human myeloma cells. The autocrine loop and increased expression of the growth factor receptors have been postulated as the mechanisms of tumorigenesis. Here we show that IL-6 stimulation induced the phosphorylation of insulin-like growth factor-I (IGF-I) receptors in a human myeloma cell line, NOP2, highly expressing IL-6 receptor ␣ (IL-6R␣) and in the IL-6R␣-transfected U266 cell line. IL-6-dependent complex formation of IL-6R␣ with IGF-I receptor  was found in NOP2 where IL-6R␣ colocalized with IGF-I receptors at lipid rafts. Moreover, the IL-6-induced phosphorylation of IGF-I receptor  was not blocked by a Janus kinase 2 (Jak2) inhibitor. In addition to the activation of the signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1/2, IL-6 stimulation led to the activation of Akt, presumably following the phosphorylation of IGF-I receptors. Thus, our results suggest that in NOP2, IL-6R␣ and IGF-I receptors exist on the plasma membrane in close proximity, facilitating the efficient assembly of 2 receptors in response to IL-6. The synergistic effects of highly expressed IL-6R␣ on IGF-I receptor-mediated signals provide a novel insight into the Jakindependent IL-6 signaling mechanism of receptor cross-talk in human myeloma cells. ( IntroductionMultiple myeloma (MM) is a hematopoietic tumor characterized as the monoclonal accumulation of malignant plasma cells. The growth of myeloma cells is mediated by the autocrine and paracrine secretion of interleukin-6 (IL-6), 1,2 and IL-6 production from myeloma cells is enhanced by IL-1 3 or CD40 stimulation, 4,5 leading to accelerated autocrine growth. IL-6 also has an antiapoptotic effect on myeloma cells, 6,7 and thus, IL-6 supports the survival and expansion of myeloma cells by both stimulating cell proliferation and preventing apoptosis.IL-6 belongs to a family of IL-6 proteins, including IL-11, leukemia inhibitory factor, oncostatin M, cardiotrophin-1, and ciliary neurotrophic factor, and the receptors of these family members share gp130 as a signal transducing molecule. 8 Accordingly, some IL-6 family members can be growth factors for myeloma cells. 9 The IL-6 receptor complex consists of IL-6R␣ and gp130, and the latter is responsible for signal transduction. 8 As both IL-6R␣ and gp130 lack kinase domains, the association of gp130 with Janus kinases (Jaks) is thought to be critical for IL-6-mediated signals. The activated Jaks phosphorylate tyrosine residues in the cytoplasmic region of gp130. The phosphorylated gp130 recruits the signal transducer and activator of transcription 3 (Stat3) whose tyrosine residues are also phosphorylated by Jaks. The phosphorylated Stat3 forms dimers and translocates to the nucleus. 10,11 Another major signal transduction pathway via gp130 is the Ras-mitogen activated protein kinase (MAPK) pathway by the complex formation of Src homology 2 domain containing tyrosine phosphatase (SHP-2) and growth factor receptor binding protein-2 (G...
CD45, a receptor-type tyrosine phosphatase, is required for interleukin-6 (IL-6)-induced proliferation in human myeloma cells, which express the shortest isoform, CD45RO, but not the longest isoform, CD45RA. Here, we showed that IL-6 induced the translocation of CD45 to lipid rafts in an isoform-dependent manner. In myeloma cells, CD45RO was translocated to lipid rafts more rapidly than CD45RB, but exogenously expressed CD45RA was not translocated. When an IL-6R␣-transfected B-cell line was stimulated with IL-6, CD45RA was not translocated, although CD45RB was. We further confirmed that the translocated CD45 bound to IL-6R␣, Lyn, and flotillin-2, and this was followed by the dephosphorylation of the negative regulatory Tyr 507 of Lyn. CD45 also bound to phosphoprotein associated with glycosphingolipid-enriched microdomains (PAGs), which were subsequently dephosphorylated, resulting in the release of C-terminal src kinase (Csk) from lipid rafts. Therefore, these results indicate that a rapid translocation of CD45RO to lipid rafts may be responsible for IL-6-induced proliferation, and that the change from CD45RA to CD45RO confers the ability to respond to IL-6 in human myeloma cells. IntroductionMultiple myeloma is a B-lineage cell malignancy characterized by the accumulation of monoclonal plasma cells in the bone marrow. We and other groups have found that interleukin-6 (IL-6) is a growth factor for human myeloma cells. 1-3 IL-6 also plays a crucial role in the onset of plasma cell tumors in mice. 4 Myeloma cells isolated from bone marrow aspirates of patients with multiple myeloma show heterogeneity in their phenotypes. Joshua et al 5 reported that CD45 ϩ immature myeloma cells had a higher labeling index than CD45 Ϫ mature myeloma cells. Also, we reported that proliferating myeloma cells are found predominantly in immature (mature plasma cell-1 [MPC-1 Ϫ ] CD49e Ϫ ) CD45 ϩ cells rather than mature (MPC-1 ϩ CD49e ϩ ) CD45 Ϫ cells. 6 Myeloma cell lines responding to IL-6 such as U266 and ILKM2 express CD45, whereas cell lines proliferating independent of IL-6 do not express CD45. 7 Furthermore, only the U266 CD45 ϩ subpopulation responded to IL-6 by proliferating; the CD45 Ϫ subpopulation did not. 8 IL-6-responsive proliferation of CD45 ϩ U266 cells requires an active src-family kinase (SFK), Lyn. 7 These results suggest that the interaction of CD45 with Lyn is essential for IL-6-induced proliferation in conjunction with the well-studied Janus kinase (JAK)-signal transducer and activator of transcription (STAT), and Ras-mitogen activated protein kinase (MAPK) pathways after the binding of IL-6 to IL-6 receptor alpha (IL-6R␣) and following the recruitment of gp130 in myeloma cells.CD45, a receptor-type protein tyrosine phosphatase, is ubiquitously expressed in all nucleated hematopoietic cells. 9 Genetic defects of CD45 in mice 10 and humans 11 cause severely combined immunodeficiency that demonstrates the essential role of CD45 in the immune system, especially for the activation and development of lymphocytes. CD...
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