Tomhave E D, Richardson R M, Didsbury J R, Menard L, Snyderman R, Ali H
Department of Medicine, Duke University Medical Center, Durham, NC 27710.
J Immunol. 1994 Oct 1;153(7):3267-75.
The formylpeptide (fMLP) and C5a chemoattractants were previously shown to cross-desensitize each other's ability to mobilize Ca2+ in leukocytes but not to affect nonchemoattractant Ca(2+)-mobilizing receptors, and vice versa. Our data show that all receptors studied underwent homologous desensitization. Interestingly, peptide chemoattractants (fMLP, C5a, and IL-8) desensitized each other's Ca(2+)-mobilizing responses, but had no effect on a Ca(2+)-mobilizing purinergic receptor. Lipid chemoattractant receptors (PAF and leukotriene B4) were also desensitized by peptide chemoattractants but not vice versa. In the presence of cytochalasin B, only fMLP and C5a caused the activation of phospholipase D in intact leukocytes and enhanced desensitization of IL-8 and C5a but not fMLP receptors. To measure receptor/G protein interactions, agonist-stimulated GTP gamma S binding to leukocyte membranes was measured. Whereas all peptide receptors underwent homologous desensitization, C5a and IL-8, but not fMLP, receptors were cross-desensitized by other peptide chemoattractants. Furthermore, PMA caused inhibition of C5a- and IL-8- but not fMLP-stimulated GTP gamma S binding. These data suggest that in addition to homologous desensitization, peptide chemoattractant receptors cross-desensitize one another by at least two processes. One can be detected at the level of receptor/G-protein interaction and possibly involves receptor phosphorylation by protein kinase C. The fMLP receptor is resistant to this process. The second process is distal to receptor/G-protein interaction and utilizes an undefined pathway to cross-desensitize the Ca2+ mobilization response to all peptide chemoattractants. We propose that receptor cross-desensitization in leukocytes is orchestrated at several levels by mechanisms with selectivity for types of chemoattractant receptors.
此前研究表明，甲酰肽（fMLP）和C5a趋化因子可相互交叉脱敏，从而影响彼此在白细胞中动员Ca2+的能力，但不影响非趋化因子的Ca(2+)动员受体，反之亦然。我们的数据表明，所有研究的受体都经历了同源脱敏。有趣的是，肽趋化因子（fMLP、C5a和IL-8）可使彼此的Ca(2+)动员反应脱敏，但对Ca(2+)动员嘌呤能受体无影响。脂质趋化因子受体（PAF和白三烯B4）也可被肽趋化因子脱敏，但反之则不然。在细胞松弛素B存在的情况下，只有fMLP和C5a能在完整白细胞中激活磷脂酶D，并增强IL-8和C5a而非fMLP受体的脱敏作用。为了测量受体/G蛋白相互作用，我们检测了激动剂刺激的GTPγS与白细胞膜的结合。虽然所有肽受体都经历了同源脱敏，但C5a和IL-8受体而非fMLP受体可被其他肽趋化因子交叉脱敏。此外，佛波酯（PMA）可抑制C5a和IL-8而非fMLP刺激的GTPγS结合。这些数据表明，除了同源脱敏外，肽趋化因子受体还通过至少两个过程相互交叉脱敏。一个过程可在受体/G蛋白相互作用水平检测到，可能涉及蛋白激酶C对受体的磷酸化。fMLP受体对该过程具有抗性。第二个过程发生在受体/G蛋白相互作用之后，利用一条未明确的途径交叉脱敏对所有肽趋化因子的Ca2+动员反应。我们认为，白细胞中的受体交叉脱敏是由对趋化因子受体类型具有选择性的机制在多个水平上精心调控的。
