Cambier J, Chen Z Z, Pasternak J, Ransom J, Sandoval V, Pickles H
Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, CO.
Proc Natl Acad Sci U S A. 1988 Sep;85(17):6493-7. doi: 10.1073/pnas.85.17.6493.
Binding of ligand to B-cell membrane immunoglobulin (mIg) can lead to activation of a number of distinct biologic responses, including altered expression of genes encoding c-fos, c-myc, and Ia, as well as proliferation and immunologic tolerance. Tolerance could reflect a functional uncoupling of receptors from systems that generate intracellular second messengers (i.e., receptor desensitization). To better understand the molecular basis of immune regulation, we examined the ability of mIg to function as a signal transducer after the cell's initial contact with mIg-binding ligand. The results show that ligand binding to as little as 2-10% of mIgM or mIgD renders the cell unresponsive to ligand binding to the reciprocal isotype as judged by Ca2+ mobilization and protein kinase C translocation responses. This heterologous receptor desensitization lasts longer than 24 hr and does not reflect loss of receptor from the cell surface. Studies with the calcium ionophore ionomycin, 1,2-dioctanoyl-sn-glycerol, and the protein kinase inhibitor staurosporine indicate that both protein kinase C-dependent and protein kinase C-independent (staurosporine-insensitive) mechanisms mediate heterologous desensitization after mIg crosslinking.
配体与B细胞膜免疫球蛋白（mIg）的结合可导致多种不同生物学反应的激活，包括编码c-fos、c-myc和Ia的基因表达改变，以及增殖和免疫耐受。耐受可能反映了受体与产生细胞内第二信使的系统之间的功能性解偶联（即受体脱敏）。为了更好地理解免疫调节的分子基础，我们研究了细胞最初接触mIg结合配体后mIg作为信号转导分子的功能。结果表明，根据Ca2+动员和蛋白激酶C易位反应判断，配体与低至2%-10%的mIgM或mIgD结合会使细胞对配体与相应同种型的结合无反应。这种异源受体脱敏持续超过24小时，且不反映细胞表面受体的丢失。使用钙离子载体离子霉素、1,2-二辛酰-sn-甘油和蛋白激酶抑制剂星形孢菌素的研究表明，蛋白激酶C依赖性和蛋白激酶C非依赖性（对星形孢菌素不敏感）机制均介导mIg交联后的异源脱敏。
