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What is the Role of Soluble Cytokine Receptors in Adult T-cell Leukemia/ Lymphoma? | OMICS International
ISSN: 2329-8790
Journal of Hematology & Thromboembolic Diseases
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What is the Role of Soluble Cytokine Receptors in Adult T-cell Leukemia/ Lymphoma?

Ratiorn Pornkuna1,2, Chie Nishioka3 and Shigeki Takemoto1,4*
1Department of International Cooperation, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
2Nursing Department, Khon Kaen Regional Hospital, Khon Kaen, Thailand
3Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan
4Clinical Laboratory, National Hospital Organization Kumamoto Medical Center, Kumamoto, Japan
Corresponding Author : Dr. Takemoto S, M.D., Ph.D.
Chief of Clinical laboratory
National Hospital Organization Kumamoto Medical Center
1-5 Ninomaru, Kumamoto 860-0008, Japan
Tel: +81-(0)96-353-6501
Fax: +81-(0)96-325-2519
E-mail: [email protected]
Received July 16, 2014; Accepted August 07, 2014; Published August 15, 2014
Citation: Pornkuna R, Nishioka C, Takemoto S (2014) What is the Role of Soluble Cytokine Receptors in Adult T-cell Leukemia/Lymphoma?. J Hematol Thrombo Dis 2:154. doi:10.4172/2329-8790.1000154
Copyright: © 2014 Pornkuna R, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Abstract

Soluble cytokine receptors are products of tumor cells infected with viruses such as human T-cell leukemia virus type 1 (HTLV-1). Adult T-cell leukemia/lymphoma (ATLL) is a highly aggressive leukemia/lymphoma caused by HTLV-1. High levels of soluble cytokine receptors are detected in the serum of patients with ATLL. Matrix metalloproteinase (MMP)-9 cleaves the interleukin (IL)-2 receptor α chain (IL-2Rα, CD25), which produces soluble IL-2Rα (sIL-2R) and down-regulates the proliferative capability of T cells that encounter cancer cells. Soluble CD30 (sCD30) impairs the interaction of CD30 ligand+ cells with CD30+ cells, whereas CD30 expression integrates survival signals to NK cells. Accordingly, high level of sIL-2R and sCD30 suggest that not only does impaired tumor surveillance lead to the survival of ATLL cells, but also dysfunction of immune surveillance can cause severe infectious complications. Freshly isolated leukemic cells from acute type ATLL patients express little CD30 on the surface, and predominantly produce sCD30. Proliferating ATLL cells are thought to release sCD30, and excess sCD30 probably blocks CD30L on normal activated T cells and myeloid cells, protecting CD30+ ATLL cells from apoptosis. Regarding CD30, two types of MMPs have been reported, ADAM10 and ADAM17, and Tax expression may be associated with ADAM17 activation in HTLV-1-infected cells. Thus, soluble cytokine receptor, sCD30, is both a serum component and a functional protein. Detection of sCD30 level may be useful for detecting and monitoring Tax-expressing tumor cells in vivo.

Abstract
Soluble cytokine receptors are products of tumor cells infected with viruses such as human T-cell leukemia virus type 1 (HTLV-1). Adult T-cell leukemia/lymphoma (ATLL) is a highly aggressive leukemia/lymphoma caused by HTLV-1. High levels of soluble cytokine receptors are detected in the serum of patients with ATLL. Matrix metalloproteinase (MMP)-9 cleaves the interleukin (IL)-2 receptor α chain (IL-2Rα, CD25), which produces soluble IL-2Rα (sIL-2R) and down-regulates the proliferative capability of T cells that encounter cancer cells. Soluble CD30 (sCD30) impairs the interaction of CD30 ligand+ cells with CD30+ cells, whereas CD30 expression integrates survival signals to NK cells. Accordingly, high level of sIL-2R and sCD30 suggest that not only does impaired tumor surveillance lead to the survival of ATLL cells, but also dysfunction of immune surveillance can cause severe infectious complications. Freshly isolated leukemic cells from acute type ATLL patients express little CD30 on the surface, and predominantly produce sCD30. Proliferating ATLL cells are thought to release sCD30, and excess sCD30 probably blocks CD30L on normal activated T cells and myeloid cells, protecting CD30+ ATLL cells from apoptosis. Regarding CD30, two types of MMPs have been reported, ADAM10 and ADAM17, and Tax expression may be associated with ADAM17 activation in HTLV-1-infected cells. Thus, soluble cytokine receptor, sCD30, is both a serum component and a functional protein. Detection of sCD30 level may be useful for detecting and monitoring Tax-expressing tumor cells in vivo.
Keywords
Adult t-cell leukemia/lymphoma (atll); human t-cell leukemia virus type 1 (htlv-1); soluble cd30 (scd30); a disintegrin and metalloproteinase (adam)10; adam17.
Introduction
Adult T cell leukemia/lymphoma (ATLL) is an aggressive leukemia/lymphoma which was first proposed as a new disease entity in 1977 [1,2]. The interaction between human T-cell leukemia virus type 1 (HTLV-1)-infected cells with different types of cells appears to be one of the basic mechanisms underlying the development of HTLV-1-associated diseases [3]. This interaction may play a major role in determining and mediating clinical features of the diseases. ATLL is classified into at least four clinical subtypes: acute, chronic, smoldering, and lymphoma-type. This classification is based on the number of abnormal T cells in peripheral blood, serum lactic acid dehydrogenase level, tumor lesions in various organs, and the clinical course. Major complications of ATLL are hypercalcemia and serious infections including Pneumocystis jirovecii pneumonia, aspergillosis or candidiasis, and cytomegalovirus pneumonia. Other diseases reported to be associated with HTLV-1 infection include chronic respiratory diseases. Monoclonal proliferation of HTLV-1-infected cells is observed in some virus carriers, who are considered to be at high risk for development of ATLL [4]. Constitutive activation of signal transducer and activator of transcription (STAT) as well as functional impairment and stabilization of p53 protein found in the peripheral blood mononuclear cells (PBMCs) of ATLL patients may be one basis for ATLL development [5,6]. However, the additional factors that lead to the severe clinical conditions of ATLL patients remains to be determined.
Interleukin-2 (IL-2) is a T-cell growth factor and essential in the survival and expansion of CD4+CD25+ activated T cells in PB [7]. Among IL-2 receptor (IL-2R) complex (α, β, and γ chains), matrix metalloproteinase (MMP)-9 mediates cleavage the IL-2R α chain (IL-2Rα, CD25), which produces soluble IL-2Rα (sIL-2R) [8]. CD30, a 120 kDa type I cell surface glycoprotein, is an unusual member of the tumor necrosis factor receptor superfamily, with a membrane form and a soluble form of CD30 (sCD30) by tumor virus cells and viral infection [9]. CD30 expression depends on mitogen or viral activation and proliferation of B and T cells and tumor cells from Hodgkin lymphoma and anaplastic large cell lymphoma express CD30 [10]. Thus levels of sCD30 and sIL-2R are elevated in HTLV-1 carriers and highly elevated in ATLL [11]. Furthermore, sCD30 elevation is followed by acute crisis in the indolent type of ATLL (unpublished data). Our findings suggest that soluble cytokine receptors may play an important role in the development ATLL.
Immune Suppression in ATLL
The poor prognosis of ATLL appears to result not only from the high frequency of drug-resistant ATLL cells, but also from a secondary immune deficiency, which results in a variety of opportunistic infections. Such immune suppression has also been observed in asymptomatic HTLV-1 carriers, who often show an increased frequency of cancer, and expansion of carcinoma metastases in situ [12]. In this context, our previous observation that monocyte-derived dendritic cells are functionally impaired in HTLV-1 carriers may be important [13]. In addition, it was reported that MMP-9 mediates cleavage of IL-2Rα and down-regulated the proliferative capability of cancer-encountered T cells [14], whereas HTLV-1-infected cells transit from IL-2-dependent to IL-2-independent growth via the acquisition of a constitutively activated STAT proteins [15] (Figure 1). On the other hand, expression of CD30 integrates survival signal to natural killer cells, allowing them to prevent viral spread and subsequent disintegration of secondary lymphoid tissue [16]. Accordingly, high levels of sIL-2R and sCD30 suggest that not only can impaired tumor surveillance lead to the survival of ATLL cells, but also dysfunction of immune surveillance can cause severe infectious complications.
The Role of a Disintegrin and Metalloproteinase (Adam)10 and Adam17 in Cd30 Shedding
MMPs represent the most prominent family of proteinases associated with tumorigenesis [17]. MMPs are enzymes that mediate tissue destruction and cell infiltration as well as shedding of cell surface cytokine and cytokine receptors. In addition, MMPs regulate signaling pathways that control cell growth, inflammation, or angiogenesis. Regarding CD30, two types of MMPs have been reported, ADAM10 and ADAM17 [18,19]. For instance, bortezomib causes CD30 shedding and human anti-CD30 antibody (Ab) simultaneous or preincubation with bortezomib fails to improve Ab therapy. Interestingly, CD30 ligation activates ADAM10 but not ADAM17, while ADAM17 is initiated by the protein kinase C (PKC) activation (Figure 2). CD30 shedding has been speculated to be controlled in multiple pathways, including those that activate ADAM10 and ADAM17.
Phytohemagglutinin (Pha-P) Stimulation Induces Scd30 Production by ATLL Cells
We previously reported that ATLL cells from patients expressed CD30, but that freshly isolated leukemic cells from acute type ATLL patients express little CD30 on the surface (Figure 3). Because CD30 is expressed by activated T cells, we first investigated CD25 and CD30 expression in PBMCs from healthy donors and patients with ATLL following stimulation with PHA-P for 72 h (Figure 4A and 4B). PBMCs from healthy donors express little or no CD25 or CD30 in the absence of PHA-P stimulation and CD25+CD30+ cells appear after stimulation. In contrast, CD25+CD30+ cells are detected in PBMCs from ATLL patients in the absence of stimulation. The results for CD4+CD30+ cells were similar to those for CD25+CD30+ cells. Next, we examined sCD30 levels in culture supernatants (Figure 4C). Higher sCD30 level were detected in the culture supernatant of PBMCs from ATLL patient with PHA-P stimulation compared to without stimulation, whereas low sCD30 levels were detected in healthy donors even with stimulation. We also found that strong stimulation with PHA-P (and anti-CD3) suppressed the proliferation of PBMCs from ATLL patients (and HTLV-1 carriers) (Supplementary figure 1 and 2). Thus, the responses are different between PBMCs from ATLL patients (HTLV-1 carriers) and healthy donors under condition of T cell activation. Our findings suggest that ATLL cells predominantly express sCD30, which plays a pivotal role in ATLL tumorigenesis.
Possible Pathways for Adam10 and Adam17 Activation In ATLL
More than 50 years are required for HTLV-1 carriers to develop ATLL, but the reasons for this long lag period are not known. The phenotype of ATLL cells is mature CD4+CD25+ T cells. HTLV-1-infected T cells produce cytokines and soluble cytokine receptors. Subsequently, soluble cytokine receptors may support clonal proliferation and invasion of ATLL cells, creating a tumor microenvironment.
sCD30 binds to CD30 ligand (CD30L) with high affinity, decreases the availability of CD30L on lymphocytes, and blocks apoptosis of CD30+ tumors [20]. Su et al. also reported that CD30 inhibits T-cell proliferation via a CD30 signaling pathway [21]. CD30L is expressed on activated T cells, granulocytes, eosinophils as well as neoplasms with an activated peripheral T-cell phenotype including ATLL (2 positive / 2 tested) [22]. In our patient with acute type ATLL, sCD30 levels increase according to the increasing number of ATLL cells. However, we detected no CD30L expression of leukemic cells from PB (data not shown). Thus, proliferating ATLL cells are thought to release sCD30, and excess sCD30 probably blocks CD30L on normal activated T cells and myeloid cells, protecting CD30+ ATLL cells from apoptosis.
Tax is a 40-kDa nuclear phosphoprotein that transactivates the transcription of HTLV-1 genome and a variety of cellular genes such as IL-2 and IL-2Rα [23]. Tax interacts with PKC and stimulates membrane translocation and triggering of the PKC pathway [24]. Actually, Okada S, et al. showed that sCD30 levels are 5 times higher in supernatant of MT-2 (Tax highly expressing cell line) than MT-4 (Tax lower expressing cell line), whereas CD30 was highly expressed on the surfaces of MT-4 [25,26]. Furthermore, Rabson AB, et al. reported that T cell activation cooperates with Tax for cellular gene expression [27,28]. It is suggested that enhancing sCD30 production results from synergistic activation by PHA and Tax (Figure 4C). Thus, Tax expression may be associated with ADAM17 activation in HTLV-1-infected cells (Figure 5). On the other hand, sCD30 itself may stimulate CD30 shedding via sCD30/anti-CD30 antibody immune complexes. sCD30/CD153 (CD30 ligand) immune complex may also play a role.
Conclusion and Future Study
The soluble cytokine receptor, sCD30, is not only a serum component but also a functional protein. The serum level of sCD30 could be used to detect and monitor Tax-expressing tumor cells in vivo.
Acknowledgements
We would like to thank the member of the Department of Hematology at NHO Kumamoto Medical Center and the Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University for collaboration.
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