Shuichi Murakami

Interleukin‐4 inhibits the production of interleukin‐1 by adult T‐cell leukemia cells

Abstract: Freshly isolated leukemic cells from patients with adult T‐cell leukemia (ATL) produce high levels of interleukin‐1 (IL‐1), which is believed to play an important role in neutrophilia, elevation of C‐reactive protein, osteolytic bone lesions, hypercalcemia, and fever in ATL. However, relatively little is known regarding the regulatory mechanism of IL‐1 production in ATL. Interleukin‐4 (IL‐4) affects the monocytes‐ and neoplastic cells‐mediated cytokine production. In this study, we investigated the effect of IL‐4 on IL‐1 α and IL‐1 β production by ATL cells in vitro. IL‐4 was found to markedly inhibit the release of IL‐1 α and IL‐1 β into the conditioned medium in a dose‐dependent manner. Northern blot analysis of steady‐state IL‐1 mRNA demonstrated that IL‐4 treatment of ATL cells resulted in a reduction of IL‐1 mRNA. These results support the notion that ATL cells spontaneously produce IL‐1 α and IL‐1 β; however, such production can be inhibited by the immunomodulating agent, IL‐4. IL‐4 may play an important regulatory role in the production of IL‐1 in ATL.

Interleukin‐1α as an autocrine growth factor for acute lymphoblastic leukaemia cells

Summary We describe a case of B‐lineage acute lymphoblastic leukaemia (ALL) with proliferation of leukaemic cells through an interleukin‐1α (IL‐lα) autocrine mechanism. Flow cytometric analysis using the IL‐1 receptor type II (IL‐1Rt II) monoclonal antibody (mAb) demonstrated the expression of the IL‐1Rt II on leukaemic cells; this is the first report in IL‐1RtII‐positive freshly isolated ALL cells from a patient. In accordance with the expression of IL‐1RtII, the leukaemic cells proliferated in response to exogenous IL‐1α. In addition, anti‐IL‐1α mAb markedly inhibited the spontaneous cell proliferation. Furthermore, Northern blot analysis detected IL‐1α mRNA without any stimulation. These observations suggest that IL‐1α may play an important role as an autocrine growth factor in some cases of ALL.

Enhancing Effect of Interleukin‐2 on Production of Parathyroid Hormone‐related Protein by Adult T‐Cell Leukemia Cells

Leukemic cells from patients with adult T‐cell leukemia (ATL) can produce a calcium‐regulating protein, parathyroid hormone‐related protein (PTHrP). Moreover, it has been reported that ATL cells produce some cytokines besides PTHrP and that these cells respond to the T‐cell growth factors, interleukin‐2 (IL‐2) and interIenkin‐4 (IL‐4). To elucidate whether PTHrP produced by ATL cells is regulated by IL‐2 or IL‐4, we investigated the in vitro effects of IL‐2 and IL‐4 on the release of PTHrP. IL‐2 increased the release of PTHrP into the conditioned medium from leukemic cells in some, but not all, ATL patients; however, IL‐4 did not affect the PTHrP release. PTHrP messenger RNA (mRNA) levels were increased in ATL cells cultured in the presence of IL‐2. These data suggest that IL‐2 plays a role in the regulation of hypercalcemia by enhancing the production of PTHrP in ATL patients.

LACK OF INTERLEUKIN-4 MRNA EXPRESSION IN ADULT T-CELL LEUKEMIA CELLS

To the Editor: Human T-cell leukemia virus type I (HTLV-I) has been identified as the infectious agent responsible for adult T-cell leukemia (ATL) (1). HTLV-I genome encodes a protein, Tax, that transactivates viral long terminal repeat-directed transcription and a variety of cellular genes such as interleukin (1L)-2 and IL-2 receptor ct chain (2, 3), and granulocyte-macrophage colony-stimulating factor, IL-3 and IL-4 (4). We have previously reported that leukemic cells from some ATL patients proliferated in response to exogenous IL-4 and constitutively expressed IL-4 receptors (5 , 6). Therefore, it may be possible that tax gene is involved in the activation of IL-4 gene in the leukemic cells from ATL patients, and that an IL4/IL-4 receptor autocrine mechanism works in the proliferation of ATL cells. We also reported that IL-4 was not detected in the culture supernatants of ATL cells by enzyme-linked immunosorbent assay (5 ) . However, the question arises as to whether ATL cells produce small but sufficient quantities of IL-4 for growth that are undetectable by conventional assay procedures. Moreover, it is possible that these ATL cells produce IL-4 that is not secreted and that would not be detected in extracellular medium. A more direct answer to this question could be obtained from a study of IL-4 mRNA assayed by a highly sensitive, yet specific reverse transcriptionpolymerase chain reaction (RT-PCR) technique for amplification of minute quantities of cellular mRNA. Eleven patients with ATL were studied. One patient (patient 10) was in chronic type, and the others were in acute type. The mononuclear cells were separated from blood of 10 ATL patients and a lymph node of 1 ATL patient (patient 11) by centrifugation on LSM solution (Litton Bionetics, Kensington, MD). CD4-positive (ATL) cells were more than 90 % of the mononuclear cells of samples, as evaluated by flow cytofluorometry. Total RNA was isolated as previously described by using the single-step isolation procedure (7). We have analyzed tax and IL-4 mRNA by complementary DNA

Ki-1 Lymphoma with Nodular Involvement in Liver and Spleen: Possible Role of Cytokines in Systemic Manifestation of Fever and Leukocytosis

Ki-1 lymphoma, a subset of non-Hodgkin’s lymphoma (NHL), usually presents with lymphadenopathy or skin involvement as the first manifestation (1–12). There are a few reports that described extranodal involvement; however, it is extremely rare that Ki-1 lymphoma presents with multiple nodular involvement in the liver and spleen in the early phase of the disease (5–15). Furthermore, there are only a few reports that have demonstrated increased cytokine levels in serum, such as interleukin (IL-6) and granulocyte colony-stimulating factor (G-CSF) and their contribution to certain clinical manifestations in patients with Ki-1 lymphoma (16–19). Here, we report a case of Ki-1 lymphoma with some unique onset features including tumor localization in the liver and spleen as well as the clinical manifestations suggestive of systemic inflammation, which were most likely attributable to increased levels of cytokines.

Characterization and regulation of interleukin-4 receptor in adult T-cell leukemia cells

We studied the expression of the receptor of interleukin (IL)‐4, one of the T cell growth factors, on fresh peripheral blood leukemic cells from adult T‐cell leukemia (ATL) patients. Flow cytofluorometric analysis with a monoclonal antibody to the IL‐4 receptor (IL‐4R) were used to investigate whether expression of IL‐4R on ATL cells is different from that on normal lymphocytes and other types of leukemic cells. Leukemic cells from acute type ATL patients synthesize IL‐4R without stimulation, at levels much higher than normal resting lymphocytes and other types of leukemic cells. Furthermore, leukemic cells from acute type ATL showed higher IL‐4R expression than that of chronic type ATL or human T‐cell leukemia virus type I carriers. In addition, there was correlation between expression of IL‐4R on the cell surface and the proliferative response to IL‐4. Both IL‐4 and IL‐2 induced upregulation of IL‐4R on activated normal T cells but not on ATL cells. These results suggest that abnormal expression of IL‐4R may display different biological activities in ATL compared with other types of leukemia. Furthermore, the high expression of IL‐4R in ATL may be involved in the proliferation of leukemic cells and the leukemogenesis in this disease.

An HTLV-I carrier who developed CD4 + T-CLL expressed the IL-2 receptor β chain alone without expressing the α chain

Summary. We describe a case of T‐chronic lymphocytic leukaemia (T‐CLL) with monoclonal proliferation of CD3 + 4 + 8 — T cell expressing the interleukin 2 receptor (IL‐2R) β chain without expressing the α chain. Southern blot analysis of T‐cell receptor β chain gene revealed rearranged bands. The serum antibody was positive against human T‐cell lymphotropic virus type I (HTLV‐1)‐associated antigens, but monoclonal integration of proviral DNA was not detected in the leukaemic cells. In accordance with the expression of IL‐2R β chain, the leukaemic cells proliferated in response to exogenous IL‐2 without prior stimulation. However, culture supernatants of these cells did not show IL‐2 activity. Since the role of the IL‐2R β chain in freshly isolated cells from T‐CLL patients is not well understood, detailed analysis of this case would give us valuable information on the role of IL‐2/ IL‐2R system in the proliferation of the leukaemic T cells.