A new interferon, limitin, displays equivalent immunomodulatory and antitumor activities without myelosuppressive properties as compared with interferon-α

Kawamoto, Shin-ichiro; Oritani, Kenji; Asakura, Eiji; Ishikawa, Jun; Koyama, Mamoru; Miyano, Kenmi; Iwamoto, Minori; Yasuda, Shin-ichiro; Nakakubo, Hirosi; Hirayama, Fumihiro; Ishida, Naoko; Ujiie, Hidetoshi; Masaie, Hiroaki; Tomiyama, Yoshiaki

doi:10.1016/j.exphem.2004.06.008

Cited by 11 publications

(12 citation statements)

References 37 publications

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“…2. Similar dose requirement between IFN-ζ/limitin and IFN-α was observed in the enhancement of cytotoxic T-lymphocyte activity and the augmentation of MHC class I expression [10]. The growth inhibition of a myelomoncytic leukemia cell line WEHI3 and a murine lymphoblast cell line L1210 also required similar dose of IFN-ζ/limitin and IFN-α [10].…”

Section: Comparison Between Ifn-ζ ζ/Limitin and Ifn-α αmentioning

confidence: 67%

“…The growth inhibition of a myelomoncytic leukemia cell line WEHI3 and a murine lymphoblast cell line L1210 also required similar dose of IFN-ζ/limitin and IFN-α [10]. However, IFN-ζ/limitin did not suppress CFU-GM or BFU-E colony formation while IFN-α did [10]. Much higher concentrations of IFN-ζ/limitin than IFN-α were required for the suppression of CFU-IL7 and CFU-Meg colony formation [9,10].…”

Section: Comparison Between Ifn-ζ ζ/Limitin and Ifn-α αmentioning

confidence: 99%

“…However, IFN-ζ/limitin did not suppress CFU-GM or BFU-E colony formation while IFN-α did [10]. Much higher concentrations of IFN-ζ/limitin than IFN-α were required for the suppression of CFU-IL7 and CFU-Meg colony formation [9,10]. Approximately 30% of CFU-GM and 50% of BFU-E in bone marrow were reduced when 4,000 inter-248 Fig.…”

Section: Comparison Between Ifn-ζ ζ/Limitin and Ifn-α αmentioning

confidence: 99%

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IFN-? limitin: a member of type I IFN with mild lympho-myelosuppression

Oritani

Kanakura

2005

J Cellular Mol Med

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Interferon (IFN)‐ζlimitin has been considered as a novel type I IFN by the Nomenclature Committee of the International Society for Interferon and Cytokine Research. IFN‐ζlimitin shows some sequence homology with IFN‐α and IFN‐β, has a globular structure with five α‐helices and four loops, and recognizes IFN‐α/β receptor. Although IFN‐ζlimitin displays antiviral, immunomodulatory, and antitumor effects, it has much less lymphomyelosuppressive activities than IFN‐α. Treatment of cells with type I IFNs induces and/or activates a number of molecules, which regulate cell cycle and apoptosis. It is noteworthy that IFN‐ζlimitin activates the Tyk2‐Daxx and Tyk2‐Crk pathways weaker than IFN‐α. Because experiments using antisense oligonucleotides have revealed their essential role in type I IFN‐related suppression of lympho‐hematopoiesis, little ability of IFN‐ζlimitin to activate the Tyk2‐dependent signaling pathway may explain its uniquely narrow range of biological activities. Further analysis of structure‐function relationship of type I IFNs will establish an engineered cytokine with useful features of IFN‐ζlimitin.

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Section: Comparison Between Ifn-ζ ζ/Limitin and Ifn-α αmentioning

confidence: 67%

Section: Comparison Between Ifn-ζ ζ/Limitin and Ifn-α αmentioning

confidence: 99%

Section: Comparison Between Ifn-ζ ζ/Limitin and Ifn-α αmentioning

confidence: 99%

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IFN-? limitin: a member of type I IFN with mild lympho-myelosuppression

Oritani

Kanakura

2005

J Cellular Mol Med

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“…Drugs that target up-regulation of MxA might provide more specific anti-tumor activity and less toxicity than type I IFNs (32) or even a new anti-tumor interferon, limitin (52). To develop an MxA-targeted small molecule, we employed an MxA promoter-reporter system in a high-throughput format to screen for inducers of MxA expression.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Tumor Cell Motility by the Interferon-inducible GTPase MxA

Mushinski

Nguyen²,

Stevens

et al. 2009

Journal of Biological Chemistry

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To identify pathways controlling prostate cancer metastasis we performed differential display analysis of the human prostate carcinoma cell line PC-3 and its highly metastatic derivative PC-3M. This revealed that a 78-kDa interferon-inducible GTPase, MxA, was expressed in PC-3 but not in PC-3M cells. The gene encoding MxA, MX1, is located in the region of chromosome 21 deleted as a consequence of fusion of TMPRSS2 and ERG, which has been associated with aggressive, invasive prostate cancer. Stable exogenous MxA expression inhibited in vitro motility and invasiveness of PC-3M cells. In vivo exogenous MxA expression decreased the number of hepatic metastases following intrasplenic injection. Exogenous MxA also reduced motility and invasiveness of highly metastatic LOX melanoma cells. A mutation in MxA that inactivated its GTPase reversed inhibition of motility and invasion in both tumor cell lines. Coimmunoprecipitation studies demonstrated that MxA associated with tubulin, but the GTPase-inactivating mutation blocked this association. Because MxA is a highly inducible gene, an MxAtargeted drug discovery screen was initiated by placing the MxA promoter upstream of a luciferase reporter. Examination of the NCI diversity set of small molecules revealed three hits that activated the promoter. In PC-3M cells, these drugs induced MxA protein and inhibited motility. These data demonstrate that MxA inhibits tumor cell motility and invasion, and that MxA expression can be induced by small molecules, potentially offering a new approach to the prevention and treatment of metastasis.

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“…Roisman and others have suggested that differences in binding to IFNAR1 may underlie the striking differences between type I IFNs in cellular activities. Indeed, the high ratio of antiviral to antiproliferative activity exhibited by the B9X series is reminiscent of limitin, a recently discovered member of the type I IFN family with a similar activity profile (17). Given that B9X14 and B9X25 differ by Ͼ20 aa from human IFN-␣2 and IFN-con1, that they were derived by explicit selection and subsequent recombination to optimize the rare phenotype of interest, and that the activity ratios are correlated with a novel pseudogene-derived motif in the IFNAR1 binding site, we suggest that these gene-shuffled IFN-␣ molecules may form a ternary complex with IFNAR1/2 that signals substantially differently than that of IFN-con1 or IFN-␣2.…”

Section: Implications For Models Of the Ifn-␣:ifnar1:ifnar2 Ternary Cmentioning

confidence: 99%