A NOVEL CHIMERIC PROTEIN COMPOSED OF INTERLEUKIN-13 AND PSEUDOMONAS EXOTOXIN IS HIGHLY CYTOTOXIC TO HUMAN CARCINOMA-CELLS EXPRESSING RECEPTORS FOR INTERLEUKIN-13 AND INTERLEUKIN-4
A NOVEL CHIMERIC PROTEIN COMPOSED OF INTERLEUKIN-13 AND PSEUDOMONAS EXOTOXIN IS HIGHLY CYTOTOXIC TO HUMAN CARCINOMA-CELLS EXPRESSING RECEPTORS FOR INTERLEUKIN-13 AND INTERLEUKIN-4
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DOI：
10.1074/jbc.270.28.16775
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发表时间：
1995-07-14
影响因子：
4.8
通讯作者：
PURI, RK
中科院分区：
文献类型：
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作者：
DEBINSKI, W;OBIRI, NI;PURI, RK
嵌合蛋白提供了一个独特的机会，靶向治疗性细菌毒素的特定细胞的子集。我们已经产生了一种新的重组嵌合毒素组成的人白细胞介素13（hIL 13）和假单胞菌外毒素A（PE）突变体，PE 38 QQR。hIL 13-PE 38 QQR嵌合体对来源于几种人上皮癌如胃腺癌、结肠癌和皮肤癌的细胞系具有高度细胞毒性。hIL 13-PE 38 QQR的细胞毒性作用仅在配体-受体复合物内化时发生，其被过量的hIL 13阻断，但不被过量的hIL 2阻断。这种作用不仅仅是hIL 13特异性的，因为过量的hIL 4也阻断hIL 13毒素的细胞毒性。相反，hIL 13阻断hIL 4-PE 38 QQR嵌合体的细胞毒性。结合研究表明，hIL 13竞争性取代癌细胞上I-126标记的hIL 4-PE 38 QQR。这些结果表明，IL 4和IL 13竞争所研究的人细胞系上的共同结合位点。尽管存在这种竞争，但hIL 4而不是hIL 13降低了对hIL 13-和hIL 4-PE 38 QQR的细胞毒性敏感的恶性细胞中的蛋白质合成。我们的研究结果表明，一个频谱的人类癌表达IL 13的结合位点。此外，hIL 13和hIL 4竞争竞争结合配体后内化的受体形式。因此，癌细胞是研究这两种生长因子受体的有趣模型。最后，hIL 13-PE 38 QQR可能是治疗几种恶性肿瘤的有用试剂。
Chimeric proteins provide a unique opportunity to target therapeutic bacterial toxins to a subset of specific cells. We have generated a new recombinant chimeric toxin composed of human interleukin 13 (hIL13) and a Pseudomonas exotoxin A (PE) mutant, PE38QQR. The hIL13-PE38QQR chimera is highly cytotoxic to cell lines derived from several human epithelial carcinomas such as adenocarcinoma of stomach, colon, and skin. The cytotoxic action of hIL13-PE38QQR, which can only occur upon internalization of ligand-receptor complex, is blocked by an excess of hIL13 but not of hIL2. This action is not solely hIL13-specific because an excess of hIL4 also blocks the cytotoxicity of hIL13 toxin. Conversely, hIL13 blocks the cytotoxicity of a hIL4-PE38QQR chimera. Binding studies showed that hIL13 displaces competitively I-126-labeled hIL4-PE38QQR on carcinoma cells. These results indicate that IL4 and IL13 compete for a common binding site on the studied human cell lines. Despite this competition, hIL4 but not hIL13 decreased protein synthesis in malignant cells susceptible to the cytotoxicity of both hIL13- and hIL4-PE38QQR. Our results suggest that a spectrum of human carcinomas express binding sites for IL13. Furthermore, hIL13 and hIL4 compete reciprocally for a form of the receptor that is internalized upon binding a ligand. Thus, cancer cells represent an interesting model fbr studying receptors for these two growth factors. Finally, hIL13-PE38QQR may be a useful agent in the treatment of several malignancies.