Immunoregulatory properties of ISG15, an interferon-induced cytokine
Immunoregulatory properties of ISG15, an interferon-induced cytokine
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DOI：
10.1073/pnas.93.1.211
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发表时间：
1996-01-09
影响因子：
11.1
通讯作者：
Borden, EC
中科院分区：
文献类型：
--
作者：
DCunha, J;Knight, E;Borden, EC
ISG15是一种具有独特初级氨基酸序列的15 kda蛋白，受干扰素(IFN) α和IFN- β转录调控。由于ISG15可在多种细胞类型中合成，并由人单核细胞和淋巴细胞分泌，我们假设ISG15可能调节免疫细胞功能，ISG15以剂量依赖的方式刺激b -缺失淋巴细胞增殖，低至1 ng/ml （58 pM）的ISG15诱导显著增殖。在6-7天内，b -缺失淋巴细胞对[H-3]胸苷结合的最大刺激发生，ISG15处理的b -缺失淋巴细胞培养的免疫表型显示，自然杀伤（NK）细胞（CD56(+)）扩增了26倍。在细胞毒性试验中，ISG15是一种有效的细胞溶解活性诱导剂，针对K562（每10(6)个细胞100个溶解单位）和Daudi（每10(6)个细胞80个溶解单位）肿瘤细胞靶标。表明ISG15增强了淋巴因子激活的杀手样活性。isg15诱导的NK细胞增殖需要T酸性NK细胞共培养，提示可溶性因子(s)是必需的。isg15处理的细胞培养上清中细胞因子的测定表明ifn - γ的产生（bbb700单位/ml）。未检出白细胞介素2和白细胞介素12。ifn - γ本身不能刺激淋巴细胞增殖和淋巴因子激活的杀伤细胞活化。此外，ISG15处理后的T淋巴细胞通过逆转录- pcr检测到ifn - γ mRNA的诱导表达，而NK细胞则没有。增强NK细胞增殖、增强非主要组织相容性复合物、限制细胞毒性以及诱导T细胞产生ifn - γ，这表明ISG15是细胞因子级联反应的一员，并表明它可能负责放大和指导ifn - α或ifn - β的一些免疫调节作用。
ISG15 is a 15-kDa protein of unique primary amino acid sequence, which is transcriptionally regulated by interferon (IFN) alpha and IFN-beta. Because it is synthesized in many cell types and secreted from human monocytes and lymphocytes, we postulated that ISG15 might act to modulate immune cell function, ISG15 stimulated B-depleted lymphocyte proliferation in a dose-dependent manner with significant proliferation induced by amounts of ISG15 as low as 1 ng/ml (58 pM). Maximal stimulation of [H-3]thymidine incorporation by B-depleted lymphocytes occurred at 6-7 days, Immunophenotyping of ISG15-treated B-depleted lymphocyte cultures indicated a 26-fold expansion of natural killer (NK) cells (CD56(+)), In cytotoxicity assays, ISG15 was a potent inducer of cytolytic activity directed against both K562 (100 lytic units per 10(6) cells) and Daudi (80 lytic units per 10(6) cells) tumor cell targets, indicating that ISG15 enhanced lymphokine-activated killer-like activity. ISG15-induced NK cell proliferation required coculturing of T acid NK cells, suggesting that soluble factor(s) were required. Measurement of ISG15-treated cell culture supernatants for cytokines indicated production of IFN-gamma (>700 units/ml). No interleukin 2 or interleukin 12 was detected. IFN-gamma itself failed to stimulate lymphocyte proliferation and lymphokine-activated killer cell activation, Further, induced expression of IFN-gamma mRNA was detected by reverse transcription-PCR in T lymphocytes after ISG15 treatment but not in NK cells. Enhancement of NK cell proliferation, augmentation of non-major histocompatibility complex-restricted cytotoxicity, and induction of IFN-gamma from T cells identify ISG15 as a member of the cytokine cascade and suggest that it may be responsible for amplifying and directing some of the immunomodulatory effects of IFN-alpha or IFN-beta.