Superantigen‐induced cytokines suppress growth of human colon‐carcinoma cells

Dohlsten, Mikael; Sundstedt, Anette; Björklund, M; Hedlund, Gunnar; Kalland, Terje

doi:10.1002/ijc.2910540321

Cited by 59 publications

(47 citation statements)

References 23 publications

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“…In this study, we used a well established model of superantigen-induced T cell tolerance (8,12,13,34,35) to investigate downstream defects in TCRmediated regulation of the IL-2-gene in tolerant CD4 ϩ T cells. It has previously been shown that IL-2 protein expression is strongly reduced at all times in tolerant (3ϫ SEA) compared with activated (1ϫ SEA) T cells, both in culture supernatants and in serum samples (8,13) (data not shown).…”

Section: Tolerant Cd4 ϩ T Cells Express Altered Nf B Binding To the Bmentioning

confidence: 99%

Bcl-3 and NFκB p50-p50 Homodimers Act as Transcriptional Repressors in Tolerant CD4+ T Cells

Grundström

Anderson

Scheipers

et al. 2004

Journal of Biological Chemistry

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The transcriptional events that control T cell tolerance are still poorly understood. To investigate why tolerant T cells fail to produce interleukin (IL)-2, we analyzed the regulation of NF B-mediated transcription in CD4 ؉ T cells after tolerance induction in vivo. We demonstrate that a predominance of p50-p50 homodimers binding to the IL-2 promoter B site in tolerant T cells correlated with repression of NF B-driven transcription. Impaired translocation of the p65 subunit in tolerant T cells was a result from reduced activation of I B kinase and poor phosphorylation and degradation of cytosolic I Bs. Moreover, tolerant T cells expressed high amounts of the p50 protein. However, the increased expression of p50 could not be explained by activation-induced de novo synthesis of the precursor p105, which was constitutively expressed in tolerant T cells. We also demonstrate the exclusive induction of the I B protein B cell lymphoma 3 (Bcl-3) in tolerant T cells as well as its specific binding to the NF B site. These results suggest that the cellular ratio of NF B dimers, and thus the repression of NF B activity and IL-2 production, are regulated at several levels in tolerant CD4 ؉ T cells in vivo.Induction of T cell tolerance may result in either deletion or anergy, the latter being characterized by a block in proliferation and diminished expression of Th1 cytokines, particularly interleukin-2 (IL-2) 1 (1). Although T cell anergy has been described both in vitro and in vivo (2-5), recent studies have shown that rather than being functionally inert, the anergic T cells may adopt the role of regulatory T cells with a Tr1-like phenotype (6, 7). Importantly, anergic T cells may be functionally regulated at several different levels, e.g. in vivo tolerized T cells may neither produce IL-2 nor respond to signaling through the IL-2 receptor (8).Because the failure of tolerant T cells to produce IL-2 is a hallmark of anergy, it is particularly important to delineate the molecular explanation for this defect. Downstream of the T cell receptor (TCR), several intracellular signaling pathways converge at the level of transcriptional regulation of the IL-2 gene. AP-1, NFAT, and NF B families of transcription factors are essential in T cell activation as coordinators of IL-2 transcription (9) and tolerant CD4 ϩ T cell clones as well as in vivo tolerized T cells possess reduced AP-1 binding to the IL-2 promoter (10 -12). In addition, we have previously shown that CD4 ϩ T cells from mice tolerized in vivo express qualitative alterations in the composition of the NF B complex (13). Defective NF B expression is also a feature of tolerant B cells (14,15).The NF B family consists of five members, p65, c-rel, RelB, p105/p50, and p100/p52, and the NF B complex is formed by hetero-or homodimerization of these different proteins (16). p65, c-rel, and RelB are synthesized as mature proteins and contain transactivation domains, whereas p105/p50 and p100/ p52 are produced as inactive precursor proteins and lack transactivation domains. Activa...

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Section: Tolerant Cd4 ϩ T Cells Express Altered Nf B Binding To the Bmentioning

confidence: 99%

Bcl-3 and NFκB p50-p50 Homodimers Act as Transcriptional Repressors in Tolerant CD4+ T Cells

Grundström

Anderson

Scheipers

et al. 2004

Journal of Biological Chemistry

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“…Cytokines can suppress tumor growth both directly and synergistically. 31 In addition, cytokines can induce LAK activity, activate natural killer cells and macrophages, [32][33][34] facilitate penetration of high molecular weight proteins and upregulate cell adhesion molecules and MHC class II expression on tumor cells. These factors favor additional fusion protein interactions with subsequent SADCC 30,35 and recruit peripheral blood cells into this inflammatory milieu.…”

Section: Discussionmentioning

confidence: 99%

“…4 Superantigen activation of lymphocyte results in cytokines production, proliferation and cytotoxicity and can elicit systemic antitumor immunity. [5][6][7] Superantigen-based antitumor strategies may offer therapeutic promise. 8,9 However, in vivo administration of intact superantigen in sufficient therapeutic amounts risks unwanted cytotoxicity against normal cells because superantigens preferentially direct cytotoxicity against MHC II-positive cells.…”

Section: Introductionmentioning

confidence: 99%

Gene therapy by membrane-expressed superantigen for α-fetoprotein-producing hepatocellular carcinoma

Sun²,

Li³

et al. 2006

Gene Ther

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Staphylococcus enterotoxin A (SEA) is a powerful immunostimulant, which can stimulate T cells bearing certain T-cell receptor b-chain variable regions, when bound to major histocompatibility complex II molecules. In vivo administration of intact superantigen in sufficient therapeutic amounts risks unwanted cytotoxicity against normal cells. In this study, we used SEA fused with CD80 transmembrane region (named as SEAtm) driven by a-fetoprotein (AFP) enhancer/ promoter to reduce toxicity and to improve safety and efficiency in the application of SEA. We demonstrated that SEAtm by adenovirus from the AFP enhancer/promoter (AdAFPSEA) could be expressed on the surface of AFPproducing cell line Hepa1-6 instead of non-AFP-producing cell lines. Hepa1-6 infected by recombinant adenovirus stimulated proliferation of splenocytes and activated CD4 + and CD8 + T cells in vitro. After AdAFPSEA was injected into the subcutaneously established hepatoma in vivo, the expression of SEA was detected in tumor tissues, which subsequently induced tumor-specific cytotoxic T cells in spleen. Moreover, hepatocellular carcinoma (HCC) xenografts were suppressed by treatment with AdAFPSEA and the survival time of treated mice was prolonged. These findings suggest that membrane-expressed SEA by adenovirus from AdAFPSEA can generate stronger local and systemic antitumor responses against HCC.

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“…In vivo, the application leads to transient expansion and subsequent death of T cells with the appropriate V b s. [7][8][9] The characteristics of superantigens can be exploited in diseases where strong immunologic responses are required. This effect has been evaluated in several preclinical [10][11][12][13][14][15][16][17][18][19][20][21][22] and clinical [23][24][25][26] studies of immunotherapeutic approaches in the treatment of cancer where superantigens were used as adjuvant or in fusion molecules with specific antibodies to enhance or maintain the immunologic response. Superantigen administration significantly enhances ineffective antitumor immune responses, resulting in potent and long-lived protective antitumor immunity.…”

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confidence: 99%

Preclinical evaluation of superantigen (staphylococcal enterotoxin B) in the intravesical immunotherapy of superficial bladder cancer

Perabo

Willert

Wirger

et al. 2005

Intl Journal of Cancer

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Superantigens are potent activators of T lymphocytes; therefore, their characteristics can be exploited in diseases where immunomodulation is known to be effective. In this study, we evaluated a new approach for the intravesical therapy of superficial bladder cancer. We investigated in coculture experiments if staphylococcal enterotoxin B (SEB)-activated PBMCs are able to induce apoptosis in human transitional cell carcinoma (TCC) cells. Additionally, we tested the toxicity and efficacy of SEB dissolved in NaCl 0.9% administered intravesically once weekly for 6 weeks in a rat bladder cancer model. To validate the coculture in vitro findings, we evaluated tumor stage, grade, apoptotic cells in the urothelium and stroma of the bladder and infiltration of the bladder wall by lymphocytes, macrophages and mononuclear cells. Coculture experiments revealed that SEB-activated PBMCs are able to kill TCC cells by inducing apoptosis. The intravesical toxicity study with a maximum dose of 100 mg/ml SEB demonstrated no side effects. In the intravesically SEB-treated animals (10 mg/ml), only 3 tumors remained vs. 15 persisting tumors in the control group. The remaining tumors of the therapy group showed a significant amount of apoptosis and granulocytes, mainly in the urothelium, whereas no relevant apoptosis or infiltration of the bladder with lymphocytes or macrophages was found in the control group. These preclinical findings suggest that SEB might be an interesting candidate for further clinical evaluation. ' 2005 Wiley-Liss, Inc.Key words: bladder cancer; superantigen; staphylococcal enterotoxin B; apoptosis; Fas ligand At initial presentation, approximately 50-70% of all bladder tumors are superficial, stage Tis (carcinoma in situ) or Ta (papillary) and T1 tumors confined to the mucosa or submucosa. 1 In the majority of these patients, tumors can be resected but have a high risk of recurrence, thus requiring adjuvant treatment. 2 The objective of intravesical therapy is to reduce recurrence or to eradicate Tis in patients when it is not possible to resect completely. The most common immunotherapeutic agent used is BCG, an attenuated strain of Mycobacterium bovis. The exact mechanism by which BCG exerts its antitumor effect remains unknown. However, cytotoxic activity of activated T lymphocytes within a complex local immune response against bladder cancer cells and secretion of several cytokines involved in the local immune response were demonstrated in in vitro cultures and in the urothelium of BCG-treated patients. [3][4][5][6] Other extremely potent activators of T lymphocytes are superantigens. Superantigens are proteins or peptide factors produced by various microorganisms like bacteria, mycoplasma or viruses. Staphylococcal enterotoxins are a family of structurally related proteins produced by Staphylococcus aureus. These compounds, m.w. 24-30 kDa, include the classical groups (A-E), the recently discovered enterotoxins G-Q and TSST-1. Streptococcal superantigens include the pyrogenic exotoxins A (and antigenic va...

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Superantigen‐induced cytokines suppress growth of human colon‐carcinoma cells

Cited by 59 publications

References 23 publications

Bcl-3 and NFκB p50-p50 Homodimers Act as Transcriptional Repressors in Tolerant CD4+ T Cells

Bcl-3 and NFκB p50-p50 Homodimers Act as Transcriptional Repressors in Tolerant CD4+ T Cells

Gene therapy by membrane-expressed superantigen for α-fetoprotein-producing hepatocellular carcinoma

Preclinical evaluation of superantigen (staphylococcal enterotoxin B) in the intravesical immunotherapy of superficial bladder cancer

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