Autocrine growth stimulation of a human T-cell lymphoma line by interleukin 2.

CCRF-CEM is a human T-cell line originally isolated from a child with acute lymphoblastic leukemia. At cell densities > 2 x 10 cells per ml, CEM cells grow in serum-free medium, but at lower cell densities the cultures rapidly undergo apoptosis, or programmed cell death. The viability of lowdensity CEM cells could be preserved by supplementing the serum-free medium with "conditioned" medium from highdensity CEM cultures, but a variety of known growth factors and lymphokines were ineffective. Fractionation ofconditioned medium by sequential chromatography on DEAE-cellulose, propyl agarose, chromatofocusing, and hydrophobic-interaction HPLC resulted in the isolation of a 60-kDa protein capable ofsustaining CEM growth in the absence ofserum. The active protein was identified as human catalase based on its amino acid sequence and composition and was subsequently shown to exhibit catalase activity and to be replaceable by human erythrocyte catalase or bovine liver catalase. Comparison of the level of intracellular catalase activity with the amount released into the culture medium demonstrated that the latter accounted for <3% of the total catalase activity present in the cell culture. These findings show that, despite its low amount, the catalase released by CEM cells, and perhaps by T cells in general, provides a critical rust Ilne of defense against hydrogen peroxide (11202) present in the extracellular milieu.Survival in aerobic conditions has required that organisms develop elaborate antioxidant defense systems to cope with potentially toxic reactive oxygen species (ROS) (1). For example, hydrogen peroxide (H202) is generated from numerous endogenous and exogenous sources including mitochondrial respiration, UV radiation, peroxigenic bacteria, and, in the immune system, from the combined actions of the NADPH oxidase and superoxide dismutase systems of phagocytes (1, 2). It has recently become apparent that ROS can have divergent effects on mammalian cell growth. In some cases low doses of H202 induced cells to undergo apoptosis, or programmed cell death (3), whereas in other cases H202 was found to promote cell proliferation (4-7). Such findings suggest that ROS may function as intracellular second messengers (8) and that growth stimulation may occur when cells are protected against excessive ROS toxicity (7).Both prokaryotes and eukaryotes produce catalase, an enzymatic antioxidant that effilciently breaks down H202 into H20 and 02. However, the extensive involvement of the glutathione peroxidase system for intracellular H202 detoxification in cells of higher organisms (9), coupled with the tenet that catalase activity is restricted to peroxisomes (7), raises the question as to what role extraperoxisomal catalase plays in antioxidant defense (10). We report here that CCRF-CEM, an acute T-lymphocytic leukemia cell line (11), displays density-dependent growth characteristics in response to cell-derived extracellular catalase and rapidly undergoes apoptosis when cultured below a critical cell density. Thes...

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“…Density-dependent growth has, in some cases, been attributed to the secretion of one or more essential cell-derived proteins (21,22). Fig.…”

Section: Resultsmentioning

confidence: 99%

Autocrine production of extracellular catalase prevents apoptosis of the human CEM T-cell line in serum-free medium.

Sandstrom

Buttke

1993

Proc. Natl. Acad. Sci. U.S.A.

168

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“…Other cells appear to regulate their growth, in part, by production of autocrine growth factors. Such is the case for IGF I in smooth muscle cells (50), platelet-derived growth factor in the osteosarcoma cell line, U-2 OS (51), transforming growth factor B in chemically transformed fibroblasts (52,53), and interleukin 2 in T lymphocytes (54,55). Several of the above growth factors influence growth of different tissues.…”

Section: Discussionmentioning

confidence: 99%

L-triiodothyronine stimulates growth by means of an autocrine factor in a cultured growth-hormone-producing cell line.

Miller¹,

Fels²,

Shapiro³

et al. 1987

J. Clin. Invest.

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L-Triiodothyronine (T3) stimulates DNA synthesis and replication of cultured GC cells, a T3-responsive growth hormone (GH)-secreting cell line. To determine whether T3 stimulates secretion of an autocrine growth factor, we compared the growthpromoting activity of medium conditioned by T3-stimulated and T3-depleted cells to that of unconditioned medium. Addition of polyclonal rabbit anti-T3 serum to T3-containing media decreased cellular T3 content by 50-70%. In unconditioned medium, anti-T3 serum decreased T3-induced cell growth and GH production by 40-70%. In conditioned medium, anti-T3 serum also effected a 45-70% decrease in induction of GH secretion but did not attenuate the growth-promoting activity. Growth-promoting activity was not detected in medium conditioned by T3-depleted cells. Thus, conditioned medium from T3-containing GC cell cultures contains growth-promoting activity that is independent of T3. Further, the induction of GC cell growth by T3 may occur, at least in part, by induction of an autocrine growth factor.

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“…In this paper, we demonstrate the mitogenic effect of IL-2 on LB cells, particularly at low fetal calf serum concentrations, suggesting that IL-2 receptors expressed on LB cells are able to generate signals leading to cell proliferation. Duprez et al (1985) have described a human T cell line (IARC 301) initially established in vitro in the absence of exogenous IL-2 and expressing functional IL-2 receptors similar to those on LB cells, which may proliferate by self-stimulation with IL-2 secreted by the cell itself.…”

Section: Discussionmentioning

confidence: 99%

Interleukin 2 exerts autocrine stimulation on murine T-cell leukaemia growth

Waldner

Montagnoli²,

Álvarez³

et al. 1997

Br J Cancer

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Summary As it has been suggested that an autocrine mechanism may control tumour cell growth, in this work cells from a spontaneous murine T lymphocyte leukaemia (LB) expressing the interleukin-2 receptor (IL-2R) (CD25) were evaluated in vitro for IL-2-mediated autocrine growth. Cells grew readily in culture and proliferation was enhanced by the addition of recombinant IL-2 but inhibited by monoclonal antibodies against either IL-2 or IL-2 receptor, in the absence of exogenous IL-2. Cyclosporin A also inhibited LB cell growth. However, when exogenous IL-2 was added together with cyclosporin A, cell proliferation proved similar to controls. Using reverse transcription polymerase chain reaction (PCR), mRNA for IL-2 was found to be present in tumour cells. Our findings support the hypothesis that LB tumour cell proliferation is mediated by an autocrine pathway involving endogenous IL-2 generation, despite the fact that these cells are not dependent on exogenous IL-2 to grow in culture.

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Autocrine growth stimulation of a human T-cell lymphoma line by interleukin 2.

Cited by 74 publications

References 37 publications

Autocrine production of extracellular catalase prevents apoptosis of the human CEM T-cell line in serum-free medium.

Autocrine production of extracellular catalase prevents apoptosis of the human CEM T-cell line in serum-free medium.

L-triiodothyronine stimulates growth by means of an autocrine factor in a cultured growth-hormone-producing cell line.

Interleukin 2 exerts autocrine stimulation on murine T-cell leukaemia growth

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