Correlation of Serum IL-2, IL-6 and IL-10 Levels With International Prognostic Index in Patients With Aggressive Non-Hodgkin’s Lymphoma

Aydin, Faruk; Yılmaz, Mustafa; Özdemir, Feyyaz; Kavgacı, Halil; Yavuz, Mustafa; Yavuz, Ali Aydın

doi:10.1097/00000421-200212000-00007

Cited by 36 publications

(29 citation statements)

References 14 publications

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“…Moreover, expression of IL-10 is elevated not only in patients with higher susceptibility to B-cell lymphoma as a result of HIV or hepatitis C virus infection 43,44 but also in asymptomatic HTLV-1 carriers and patients with T-cell lymphomas. [45][46][47] Taken together, our results suggest that deregulation of IL-10 by both functional loss of p53 and lack of iNOS activity plays an important role in nonthymic lymphomagenesis.…”

Section: Discussionsupporting

confidence: 55%

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: Discussionsupporting

confidence: 55%

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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“…In contrast, IL-10 overproduction has also been associated with autoimmune diseases, including insulitis, as demonstrated in an experimental model of diabetes-prone rodents (51); SLE (52); and neoplasia (53). For example, in non-Hodgkin's lymphoma (NHL), both IL-10 message and protein are found in B cells, and increased levels of IL-10 correlate with severity of disease (54,55). A more recent study has demonstrated that the A nucleotide at position Ϫ571 of the IL-10 promoter is associated with more aggressive forms of NHL (56).…”

Section: Discussionmentioning

confidence: 99%

Functional Analysis of −571 IL-10 Promoter Polymorphism Reveals a Repressor Element Controlled by Sp1

Steinke

Barekzi

Hagman

et al. 2004

The Journal of Immunology

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Transcriptional dysregulation of the IL-10 gene may contribute to the development and severity of autoimmune, infectious, neoplastic, and allergic diseases. A C to A base substitution has been identified at −571 bp in the IL-10 promoter and has been linked to immune diseases. The role of this polymorphism in IL-10 promoter function was assessed using luciferase reporter constructs. The presence of an A at −571 (A allele) increases promoter activity compared with that of a promoter with a C at this position (C allele). Binding of nuclear extract proteins from IL-10-producing human cell lines to DNA sequences including this base exchange and flanking sequences was demonstrated using EMSAs. Specific binding of the transcription factors Sp1 and Sp3 was demonstrated to a region immediately upstream of the polymorphism. No differences in the binding affinity of recombinant Sp1 were observed between the two forms of the promoter. Reconstitution of Sp1 expression decreased IL-10 promoter function in an Sp1-deficient cell line, demonstrating that this element functions as a repressor. The C to A base exchange relieves the repression mediated by Sp1. Individuals carrying the A allele of the IL-10 promoter may display increased synthesis of IL-10, resulting in suppressed immune responses and a modulation of their susceptibility to autoimmune, infectious, neoplastic, or atopic disease.

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“…3 Stimulation of autocrine production of IL-10 in B-1 cells has been found to promote their survival. 4 IL-10 has been found to be elevated in a variety of B-cell malignancies, including mantle cell lymphoma, 5,6 AIDS-associated B lymphoma, 7 and in some patients with chronic lymphocytic leukemia (CLL). 8 Exogenous IL-10 has been found to stimulate the proliferation of mantle cell lymphoma cells.…”

Section: Introductionmentioning

confidence: 99%

Studies in NZB IL-10 knockout mice of the requirement of IL-10 for progression of B-cell lymphoma

et al. 2004

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NZB mice develop an age-related malignant expansion of a subset of B cells, B-1 cells, with autocrine production of IL-10. IL-10, a pleiotropic cytokine with anti-inflammatory properties, is a potent growth and survival factor for malignant B cells. To further examine the in vivo requirement for IL-10 in the development and expansion of malignant B-1 clones in NZB mice, we developed a strain of homozygous IL-10 knockout (KO) mice on an NZB background. The NZB IL-10 KO mice develop peritoneal B-1 cells with approximately the same frequency as heterozygous and wild-type littermates. In contrast, the development of malignant B-1 cells in the peripheral blood and spleen, observed in wild-type NZB, rarely occurred in the NZB IL-10 KO. Phenotypic analysis of surface marker expression in splenic B cells indicated that, in contrast to the NZB with malignant B-1 splenic lymphoma, the surface marker expression of NZB IL-10 KO splenic B cells indicated that the majority of the B cells were typical B-2 cells. In the absence of IL-10, spontaneously activated B cells and antiapoptotic gene expression were reduced and lymphoma incidence was decreased. These results indicate that IL-10 is a critical factor for the progression of this B-cell malignant disease.

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Correlation of Serum IL-2, IL-6 and IL-10 Levels With International Prognostic Index in Patients With Aggressive Non-Hodgkin’s Lymphoma

Cited by 36 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

Functional Analysis of −571 IL-10 Promoter Polymorphism Reveals a Repressor Element Controlled by Sp1

Studies in NZB IL-10 knockout mice of the requirement of IL-10 for progression of B-cell lymphoma

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