Unglaub R, Maxeiner B, Thoma B, Pfizenmaier K, Scheurich P
Klinische Arbeitsgruppe BRWTI, Max-Planck-Gesellschaft, Göttingen, Federal Republic of Germany.
J Exp Med. 1987 Dec 1;166(6):1788-97. doi: 10.1084/jem.166.6.1788.
The regulatory action of activators for protein kinase C on the specific binding capacity for recombinant human tumor necrosis factor alpha (TNF-alpha) was studied on various human cell lines. Phorbol myristate acetate (PMA) and oleyl acetyl glycerol (OAG) both are able to rapidly downregulate TNF-binding capacity of normal and malignant cells derived from various tissues. As PMA treatment did not enhance internalization of TNF-alpha-receptor complexes at 37 degrees C, and since OAG was able to downregulate TNF-binding capacity under conditions where internalization and shedding of receptor protein are prevented, we conclude that protein kinase C controls ligand affinity of the TNF-receptor protein, possibly via direct phosphorylation. Protein kinase C triggered downregulation of TNF-alpha-binding capacity concomitantly resulted in reduction of TNF-alpha sensitivity, as revealed from decreased cytotoxic action of TNF-alpha on L 929 cells and from inhibition of TNF-alpha-mediated enhancement of HLA class II antigen expression in Colo 205 cells. Restoration of TNF-binding capacity upon abrogation of protein kinase C stimulation leads to full recovery of TNF responsiveness, further supporting the close linkage of TNF-receptor expression and TNF sensitivity. These data suggest that regulation of TNF-binding capacity by protein kinase C is one of the cellular control mechanisms of TNF responsiveness.
在多种人类细胞系上研究了蛋白激酶C激活剂对重组人肿瘤坏死因子α（TNF-α）特异性结合能力的调节作用。佛波酯（PMA）和油酰乙酰甘油（OAG）均能迅速下调源自各种组织的正常细胞和恶性细胞的TNF结合能力。由于PMA处理在37℃时并未增强TNF-α受体复合物的内化，且由于OAG在防止受体蛋白内化和脱落的条件下能够下调TNF结合能力，我们得出结论，蛋白激酶C可能通过直接磷酸化来控制TNF受体蛋白的配体亲和力。蛋白激酶C引发的TNF-α结合能力下调同时导致TNF-α敏感性降低，这从TNF-α对L 929细胞的细胞毒性作用降低以及对Colo 205细胞中TNF-α介导的HLA II类抗原表达增强的抑制中得以体现。在取消蛋白激酶C刺激后TNF结合能力的恢复导致TNF反应性完全恢复，进一步支持了TNF受体表达与TNF敏感性的紧密联系。这些数据表明，蛋白激酶C对TNF结合能力的调节是TNF反应性的细胞控制机制之一。
