title: Upregulated production of IL-6, but not IL-10, by interferon-alpha induces SOCS3 expression and attenuates STAT1 phosphorylation in myeloma cells.
abstract: Interferon-alpha (IFN-alpha) is used as a treatment for multiple myeloma, although its clinical effects remain controversial. Here, we investigated whether IFN-alpha altered the autocrine production of interleukin-6 (IL-6) or IL-10, both identified as key cytokines regulating myeloma cell growth/survival, and found that IL-6, but not IL-10, induced by IFN-alpha attenuated IFN-alpha-mediated signaling in myeloma cells via an upregulated SOCS3. Using reverse transcription-polymerase chain reaction, expression of the IL-6 gene (IL-6) and IL-10 was detected in two and three of eight myeloma cell lines, respectively. When myeloma cells were cultured with IFN-alpha, an increase of IL-6 and IL-10 production was detected in IL-6-expressing and in IL-10-expressing cells, respectively. IFN-alpha inhibited the cell growth of these myeloma lines. Addition of an IL-6-neutralizing antibody prolonged the phosphorylation of STAT1 induced by IFN-alpha and significantly enhanced the cell growth suppression of IFN-alpha on IL-6-expressing cells. However, a similar blocking of IL-10 in the presence of IFN-alpha did not affect the growth/survival of IL-10-expressing cells. Interestingly, exogenous IL-6, but not IL-10, induced high levels of SOCS3 expression. Although upregulation of SOCS3 was also observed in the presence of IFN-alpha alone in IL-6-expressing cells, this expression was completely abrogated by the IL-6-neutralizing antibody. The L929 cell line transfected with SOCS3 showed the protection from the growth suppression of IFN-alpha. These results suggest that IL-6 induced by IFN-alpha plays an important role in the growth/survival of myeloma cells via an autocrine loop, and upregulated SOCS3 by IL-6 may be at least partially responsible for the IL-6-mediated inhibition of IFN-alpha signaling in myeloma cells.
authors.affiliation: Second Department of Internal Medicine, Mie University School of Medicine, Mie, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Usui
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nishii
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Katayama
authors.forename: Felipe
authors.initials: F
authors.lastname: Lorenzo V
authors.forename: Fawen
authors.initials: F
authors.lastname: Chen
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Monma
authors.forename: Takemi
authors.initials: T
authors.lastname: Otsuki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shiku
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012097:Repressor Proteins / Q000187:drug effects / Q000235:genetics*; D050794:STAT1 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D000093242:Interleukin-6 Inhibitors
chemical_list: D000906:Antibodies; D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D016753:Interleukin-10; D015850:Interleukin-6; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000093242:Interleukin-6 Inhibitors; C106644:SOCS3 protein, human; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse