Baxevanis C N, Dedousis G V, Gritzapis A D, Papadopoulos N G, Arsenis P, Katsiyiannis A, Papamichail M
Department of Immunology, Hellenic Anticancer Institute, Athens, Greece.
Immunopharmacol Immunotoxicol. 1994 May;16(2):225-45. doi: 10.3109/08923979409007092.
We examined the role of endogenously produced interleukin 1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) in lectin-induced nonspecific suppressor activity in vitro. The cultures consisted of highly purified T lymphocytes, autologous monocytes and phytohemagglutinin (PHA). Kinetic studies revealed peak levels for both TNF-alpha and IL-1 beta production 4 hr after initiation of cultures which then declined and reached minimal levels on day 3. At this time point maximal levels of interleukin-2 (IL-2) were detected which declined sharply 24 hr later. The decline in cytokine levels in culture supernatants was most probably due to their consumption by the mononuclear cells which were found to express specific receptors for IL-1 beta, (IL-1 beta R), TNF-alpha (TNF-alpha R) and IL-2 (IL-2R) after 3- and 6-days of culture. After their first cycle of production and consumption both monokines were reproduced and the events followed the same patterns as for the first cycle: both monokines were first produced and at the time point of their consumption, IL-2 production reached maximal levels. The requirement for IL-1 beta and TNF-alpha in both IL-2 production and generation of suppressor activity was shown by three different approaches which included (a) blocking of HLA-DR molecules on monocytes which prevented monokine consumption during the early stages of culture, (b) blocking of HLA-A,B,C molecules on monocytes which prevented monokine consumption and IL-2 production late in culture, and (c) neutralization of monokine activity late in culture which resulted in highly reduced IL-2 production. T lymphocytes harvested from such cultures exhibited diminished suppressor activity. Our data suggest that the generation of nonspecific suppressor cell activity in vitro represents a complex system that requires cell interactions via self-major histocompatibility complex (MHC) antigen recognition and two cycles of cytokine production, where IL-1 beta and TNF-alpha production and consumption is a prerequisite for IL-2 production. Since lectin-induced nonspecific suppressor activity in vitro is deficient in certain autoimmune disorders the data presented herein might help in understanding the cellular basis for this immunodeficiency.
我们研究了内源性产生的白细胞介素1β（IL-1β）和肿瘤坏死因子-α（TNF-α）在体外凝集素诱导的非特异性抑制活性中的作用。培养物由高度纯化的T淋巴细胞、自体单核细胞和植物血凝素（PHA）组成。动力学研究显示，培养开始后4小时，TNF-α和IL-1β的产生均达到峰值水平，随后下降，并在第3天达到最低水平。在这个时间点检测到白细胞介素-2（IL-2）的最大水平，24小时后急剧下降。培养上清液中细胞因子水平的下降很可能是由于单核细胞对它们的消耗，在培养3天和6天后发现单核细胞表达IL-1β特异性受体（IL-1βR）、TNF-α特异性受体（TNF-αR）和IL-2特异性受体（IL-2R）。在它们的第一个产生和消耗周期后，两种单核因子都再次产生，并且这些事件遵循与第一个周期相同的模式：两种单核因子首先产生，在它们被消耗的时间点，IL-2的产生达到最大水平。通过三种不同的方法证明了IL-1β和TNF-α在IL-2产生和抑制活性产生中的必要性，这三种方法包括：（a）阻断单核细胞上的HLA-DR分子，这在培养早期阻止了单核因子的消耗；（b）阻断单核细胞上的HLA-A、B、C分子，这在培养后期阻止了单核因子的消耗和IL-2的产生；（c）在培养后期中和单核因子活性，这导致IL-2的产生大幅减少。从这些培养物中收获的T淋巴细胞表现出减弱的抑制活性。我们的数据表明，体外非特异性抑制细胞活性的产生代表了一个复杂的系统，该系统需要通过自身主要组织相容性复合体（MHC）抗原识别进行细胞相互作用以及两个细胞因子产生周期，其中IL-1β和TNF-α的产生和消耗是IL-2产生的先决条件。由于在某些自身免疫性疾病中体外凝集素诱导的非特异性抑制活性存在缺陷，本文提供的数据可能有助于理解这种免疫缺陷的细胞基础。
