Receptor synergy of interleukin-6 (IL-6) and insulin-like growth factor-I in myeloma cells that highly express IL-6 receptor α

Abstract

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...

Galectin-3 Is Required for Resident Microglia Activation and Proliferation in Response to Ischemic Injury

“…These data are in agreement with previous work by Jeon et al (2010), who demonstrated that galectin-3 may exert its functions primarily through the JAK-STAT pathway. Together, our results indicate that galectin-3 deficiency leads to a defective microglia activation and defective IGF-R1 signaling/mitogenic response in microglial cells, and likely compensatory overexpression of IL-6 (Abroun et al, 2004). This may lead to an overactivation of JAK/STAT pathway and upregulation of a feedback inhibitor SOCS3 (Wormald et al, 2006).…”

“…7A-C) (***p Ͻ 0.0001). Since growing evidence suggests a crosstalk and synergy between IL-6 and IGF-R1, we further analyzed downstream IGFR1-mediated signaling events (Abroun et al, 2004;Sprynski et al, 2009).…”

Body Mass Index, Physical Activity, and Risk of Multiple Myeloma

“…Obesity is also associated with insulin resistance and other metabolic disorders that can result indirectly in the modulation of bioavailable insulin-like growth factor-I (27)(28)(29), another important growth and survival factor in multiple myeloma (30)(31)(32). Furthermore, synergy in the IL-6 and insulin-like growth factor-I pathways has been suggested by in vitro experiments on multiple myeloma cell lines (33). Thus, although BMI does not seem to correlate directly with circulating levels of insulin-like growth factor-I (29), obesityrelated increases in bioavailable insulin-like growth factor-I may further contribute to multiple myeloma pathogenesis.…”

Accelerated proliferation of myeloma cells by interleukin-6 cooperating with fibroblast growth factor receptor 3-mediated signals

“…First strand DNA was synthesized with fgfr3-RT, and either fgfr3-U or fgfr3-1 as sense primers and fgfr3-D as an antisense primer amplified the full-length fgfr3 cDNA. After confirming the nucleotide sequence of the fragments, they were transferred into the retroviral vector pRep (pMxpuro, Onishi et al, 1998) followed by retrovirus infection into U266 myeloma cell line as reported previously (Abroun et al, 2004). Sequences of the primers were as follows: fgfr3-RT: 5 0 -TGCACCAGCAGCAGGGAGGGCTGCTA-3 0 , fgfr3-U: 5 0 -CGCGCGCTGCCTGAGGACGCCG-3 0 , fgfr3-1: 5 0 -CGGCCCCCGCCCCCGCCATG-3 0 , fgfr3-D: 5 0 -TGGGGACCAGTGGCC CTTCACGTCCG-3 0 .…”