Hassuneh M R, Nagarkatti P S, Nagarkatti M
Department of Biology, Virginia-Maryland Regional College of Veterinary Medicine, Blacksburg 24061, USA.
Blood. 1997 Jan 15;89(2):610-20.
In the current study, we investigated the role of interleukin-2 (IL-2) and IL-4 as autocrine growth factors responsible for autonomous growth of four murine tumor cell lines: LSA, a radiation leukemia virus-induced T-cell lymphoma; EL-4, a chemically triggered T-cell lymphoma; PE-3T, a T-cell line that underwent spontaneous transformation ex vivo; and P815, a mastocytoma. All tumor cell lines screened constitutively expressed IL-2 receptor (IL-2R) and IL-4R genes. However, only LSA and PE-3T cells expressed IL-2 and IL-4 genes constitutively, whereas EL-4 and P815 tumor cells expressed only IL-4 but not IL-2. Monoclonal antibodies (MoAbs) against IL-2, IL-4, or a combination of these, as well as MoAbs against IL-2R significantly inhibited the proliferation of LSA but not that of other tumor cell lines ex vivo. To exclude the possibility that, in other tumor cell lines, the autocrine growth factor may interact with its receptor within the cell, the ability of antisense phosphorothioate oligonucleotides to inhibit the growth of the tumor cells was tested. The antisense phosphorothioate oligonucleotides specific for IL-2, IL-4, IL-2R beta, or IL-2R gamma chains, added in culture, could markedly inhibit the growth of LSA but not that of the other tumor cell lines screened. Inasmuch as IL-2R beta and IL-2R gamma subunits also serve as a component of the receptors for IL-4, IL-7, IL-9, and IL-15, the above data suggested that such cytokine redundancy was not responsible for autonomous growth of the other tumor cell lines. Addition of exogenous IL-2 or IL-4 to the tumor cell cultures caused significant enhancement in the proliferation of PE-3T cells, whereas other cell lines were either not significantly affected or slightly inhibited from growing. Interestingly, the LSA tumor growth in nude mice was significantly inhibited after treatment of these mice with a combination of MoAbs against IL-2 and IL-4. Together, our studies show for the first time that IL-2 and IL-4 may serve as autocrine growth factors in the autonomous proliferation of tumor cells, particularly those that are retrovirally induced. Second, some tumor cell lines, despite expressing certain cytokines and their receptors constitutively, may not depend exclusively on such factors for autocrine growth.
在本研究中，我们调查了白细胞介素-2（IL-2）和IL-4作为自分泌生长因子在四种小鼠肿瘤细胞系自主生长中的作用，这四种细胞系分别为：LSA，一种辐射白血病病毒诱导的T细胞淋巴瘤；EL-4，一种化学诱导的T细胞淋巴瘤；PE-3T，一种在体外自发转化的T细胞系；以及P815，一种肥大细胞瘤。所有筛选的肿瘤细胞系均组成性表达IL-2受体（IL-2R）和IL-4R基因。然而，只有LSA和PE-3T细胞组成性表达IL-2和IL-4基因，而EL-4和P815肿瘤细胞只表达IL-4而不表达IL-2。抗IL-2、IL-4或它们的组合的单克隆抗体（MoAbs），以及抗IL-2R的MoAbs在体外显著抑制了LSA的增殖，但对其他肿瘤细胞系无此作用。为排除在其他肿瘤细胞系中自分泌生长因子可能在细胞内与其受体相互作用的可能性，测试了反义硫代磷酸酯寡核苷酸抑制肿瘤细胞生长的能力。在培养中添加针对IL-2、IL-4、IL-2Rβ或IL-2Rγ链的反义硫代磷酸酯寡核苷酸，可显著抑制LSA的生长，但对其他筛选的肿瘤细胞系无此作用。由于IL-2Rβ和IL-2Rγ亚基也是IL-4、IL-7、IL-9和IL-15受体的组成部分，上述数据表明这种细胞因子冗余并非其他肿瘤细胞系自主生长的原因。向肿瘤细胞培养物中添加外源性IL-2或IL-4可显著增强PE-3T细胞的增殖，而其他细胞系要么未受到显著影响，要么生长略有抑制。有趣的是，用抗IL-2和IL-4的MoAbs组合处理裸鼠后，LSA肿瘤在裸鼠中的生长受到显著抑制。总之，我们的研究首次表明，IL-2和IL-4可能作为自分泌生长因子参与肿瘤细胞的自主增殖，特别是那些逆转录病毒诱导的肿瘤细胞。其次，一些肿瘤细胞系尽管组成性表达某些细胞因子及其受体，但可能并非完全依赖这些因子进行自分泌生长。
