Antitumor Activity of Interleukin-18 Against the Murine T-Cell Leukemia/Lymphoma EL-4 in Syngeneic Mice

Akamatsu, Sachiko; Arai, Norie; Hanaya, Toshiharu; Arai, Shigeyuki; Tanimoto, Tadao; Fujii, Mitsukiyo; Kohno, Keizo; Micallef, Mark; Ikeda, Masao; Kurimoto, Masashi

doi:10.1097/00002371-200203001-00005

Cited by 22 publications

(15 citation statements)

References 14 publications

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“…IL-18 has preventive activity against the development of murine T-cell leukemia/lymphoma EL-4 in syngeneic mice. 48 IL-18 strongly induces iNOS in natural killer cells via induction of IFN-␥ and TNF-␣. 49 However, activation of IL-18 is downregulated by iNOS activity because IL-18 is activated by IL-1␤-converting enzyme, which is inhibited by S-nitrosylation by NO.…”

Section: Discussionmentioning

confidence: 99%

Suppression of thymic lymphomas and increased nonthymic lymphomagenesis in Trp53‐deficient mice lacking inducible nitric oxide synthase gene

Tatemichi

Tazawa

Masuda

et al. 2004

Intl Journal of Cancer

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Trp53-deficient mice spontaneously develop lymphomas, mainly of thymic origin, although the molecular mechanism remains largely unknown. As several interaction effects between p53 and iNOS have been reported, we hypothesized that iNOS activity in the thymus is causally linked to lymphomagenesis in Trp53-deficient mice. We therefore created mouse strains with different combinations of the Trp53 and iNOS genes. Western blot and histologic analyses showed that the iNOS protein was constitutively expressed in the thymus independently of Trp53 status and its expression was enhanced in Trp53 ؉/-and Trp53 -/-mice compared to Trp53 ؉/؉ mice. Homozygous disruption of iNOS decreased the incidence of thymic lymphomas by almost 40% (p ‫؍‬ 0.087) and 90% (p < 0.05) in Trp53 -/-and Trp53 ؉/-mice, respectively, compared to the respective iNOS wild-type mice but significantly (p < 0.05) increased the development of nonthymic lymphomas in Trp53 -/-and Trp53 ؉/-mice. Although iNOS gene disruption did not affect the phenotype of thymic lymphomas, absence of the iNOS gene shifted the spectrum of nonthymic lymphoma from the B-cell to the T-cell lineage. RT-PCR analysis revealed enhanced expression of IL-10, which could have a promoting effect on lymphomagenesis, even without any stimulation, in the spleen of aging mice with the gene combinations Trp53 -/-iNOS -/-and Trp53 ؉/-iNOS -/-but not Trp53 -/-iNOS ؉/؉ or Trp53 ؉/-iNOS ؉/؉ . These results suggest that iNOS could increase the development of thymic lymphomas in Trp53-deficient mice. While iNOS may have protective effects against nonthymic lymphomagenesis, the regulation of cytokine production by iNOS may be involved in the underlying mechanism of antilymphomagenesis effects in the peripheral lymphoid organ.

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Section: Discussionmentioning

confidence: 99%

Suppression of thymic lymphomas and increased nonthymic lymphomagenesis in Trp53‐deficient mice lacking inducible nitric oxide synthase gene

Tatemichi

Tazawa

Masuda

et al. 2004

Intl Journal of Cancer

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“…Intercrossing TEL-JAK2 transgenic animals with TCRα -/-mice does not shift disease phenotype or latency (N. dos Santos and J. Ghysdael, personal communication). The situation for EL-4-induced lymphoma is less clear cut, because NK cells as well as CTLs have been reported to lyse EL-4 cells (33)(34)(35).…”

Section: Figurementioning

confidence: 99%

TYK2 is a key regulator of the surveillance of B lymphoid tumors

Stoiber¹,

Kovacic²,

Schuster³

et al. 2004

J. Clin. Invest.

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Aberrant activation of the JAK-STAT pathway has been implicated in tumor formation; for example, constitutive activation of JAK2 kinase or the enforced expression of STAT5 induces leukemia in mice. We show here that the Janus kinase TYK2 serves an opposite function. Mice deficient in TYK2 developed Abelsoninduced B lymphoid leukemia/lymphoma as well as TEL-JAK2-induced T lymphoid leukemia with a higher incidence and shortened latency compared with WT controls. The cell-autonomous properties of Abelson murine leukemia virus-transformed (A-MuLV-transformed) TYK2 -/-cells were unaltered, but the high susceptibility of TYK2 -/-mice resulted from an impaired tumor surveillance, and accordingly, TYK2 -/-A-MuLV-induced lymphomas were easily rejected after transplantation into WT hosts. The increased rate of leukemia/lymphoma formation was linked to a decreased in vitro cytotoxic capacity of TYK2 -/-NK and NKT cells toward tumor-derived cells. RAG2/TYK2 double-knockout mice succumbed to A-MuLV-induced leukemia/lymphoma faster than RAG2 -/-TYK2 +/-mice. This defines NK cells as key players in tumor surveillance in Abelson-induced malignancies. Our observations provide compelling evidence that TYK2 is an important regulator of lymphoid tumor surveillance. IntroductionThe JAK-STAT pathway regulates cell proliferation, differentiation, and survival in hematopoietic cells (1, 2). Binding of a cytokine to its cognate receptor activates receptor-associated JAKs which in turn mediate the subsequent tyrosine phosphorylation of STAT proteins. Phosphorylated STAT proteins form dimers, translocate to the nucleus, and bind to specific DNA elements to induce or modulate expression of target genes. Gene knockout studies in mice underlined the vital role of the JAK-STAT pathway for hematopoiesis and other developmental processes (3).Recent interest had focused on the role of the JAK-STAT pathway in tumor formation. Aberrant activation of JAK-STAT signaling had been shown in multiple solid tumors and leukemia (4-9). In particular, STAT3 and STAT5 have drawn much attention; both transcription factors display oncogenic properties when expressed ectopically. A constitutively active mutant of STAT3 was shown to transform rat fibroblasts (10), and the enforced expression of WT STAT5 in the lymphoid lineage induced T cell leukemia in mice (11). In addition, JAK1 has been implicated in transformation by the v-abl as well as by the v-src oncogene (12, 13), and constitutive activation of JAK2 as in the TEL-JAK2 oncogene suffices to induce leukemia in mice and humans (14, 15). On the other hand, JAK1 was shown to be a tumor suppressor downstream of IFN-γ in a B lymphoid tumor model (16). A role as tumor suppressor downstream of IFN-γ has also been attributed to STAT1 (17-21). STAT1 -/-mice have been repeatedly used to study the role of IFN-γ in tumorigenesis and tumor surveillance (18,19). Recent evidence also proposed that STAT1 acted as a tumor suppressor by modulating apoptosis (22).TYK2 has been initially defined as a mediator of IFN-α/β sign...

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“…7 Recently, several reports have shown that IL-18 has potent antitumor effects when administered in animal models of lung cancer, breast cancer, sarcoma and melanoma in vivo. [7][8][9][10][11] In these models, systemic administration of IL-18 9,12 or in vivo IL-18 gene transfer 13,14 inhibited tumor growth and prolonged the survival of tumor-bearing mice. The antitumor effects of IL-18 in multiple animal models provided the rationale for investigation of recombinant human (rh) IL-18 in clinic cancer immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

Oncolytic adenovirus expressing interleukin-18 induces significant antitumor effects against melanoma in mice through inhibition of angiogenesis

Zheng

Park

et al. 2009

Cancer Gene Ther

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It has been shown that interleukin 18 (IL-18) exerts antitumor activity. In this study, we investigated whether oncolytic adenovirusmediated gene transfer of IL-18 could induce strong antitumor activity. A tumor-selective replicating adenovirus expressing IL-18 (ZD55-IL-18) was constructed by insertion of an IL-18 expression cassette into the ZD55 vector, which is based on deletion of the adenoviral E1B 55-kDa gene. It has been shown that ZD55-IL-18 exerted a strong cytopathic effect and significant apoptosis in tumor cells. ZD55-IL-18 significantly decreased vascular endothelial growth factor and CD34 expression in the melanoma cells. Treatment of established tumors with ZD55-IL-18 showed much stronger antitumor activity than that induced by ZD55-EGFP (enhanced green fluorescent protein) or Ad-IL-18. These data indicated that oncolytic adenovirus expressing IL-18 could exert potential antitumor activity through inhibition of angiogenesis and offer a novel approach to melanoma therapy.

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Antitumor Activity of Interleukin-18 Against the Murine T-Cell Leukemia/Lymphoma EL-4 in Syngeneic Mice

Cited by 22 publications

References 14 publications

Suppression of thymic lymphomas and increased nonthymic lymphomagenesis in Trp53‐deficient mice lacking inducible nitric oxide synthase gene

Suppression of thymic lymphomas and increased nonthymic lymphomagenesis in Trp53‐deficient mice lacking inducible nitric oxide synthase gene

TYK2 is a key regulator of the surveillance of B lymphoid tumors

Oncolytic adenovirus expressing interleukin-18 induces significant antitumor effects against melanoma in mice through inhibition of angiogenesis

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