Modiano J F, Kelepouris E, Kern J A, Nowell P C
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104-6082.
J Cell Physiol. 1988 Jun;135(3):451-8. doi: 10.1002/jcp.1041350312.
The importance of calcium in lymphocyte activation is well recognized, but the levels of extracellular ionized free calcium (Ca++) necessary for lymphocyte proliferation via various pathways have not been investigated in detail. We studied the ability of a lectin mitogen (PHA) and a calcium ionophore (ionomycin) to induce interleukin 2 receptors, interleukin 2 (IL2) production, and proliferation over various concentrations of extracellular Ca++. Reducing the Ca++ levels from the normal 200 microM to 10 microM in PHA-stimulated cultures partially inhibited IL2 receptor expression, IL2 production, and subsequent proliferation. At 1 microM Ca++, both IL2 activity and proliferation were eliminated, but partial IL2 receptor expression was still observed. Ionomycin did not induce any of these events in cultures where the extracellular Ca++ concentration was below 100 microM. Restoring calcium in the medium resulted in normal levels of IL2 receptor expression, IL2 activity, and proliferation when PBL were stimulated with either mitogen. Exogenous magnesium partially restored these events in PHA-stimulated cultures, but had no effect when ionomycin was used as the mitogen. These data indicate that stimulation by ionomycin is much more dependent upon the levels of extracellular Ca++ than is PHA. Extracellular calcium also appears to be necessary subsequent to IL2 receptor acquisition, since the latter was seen without IL2 activity or proliferation at very low extracellular Ca++, and IL2 failed to restore the proliferative response under these conditions. The data also suggest that PHA, but not ionomycin, can activate lymphocytes via a magnesium-dependent pathway, or that PHA has a lower specificity for divalent cation cofactors.
钙在淋巴细胞激活中的重要性已得到充分认识，但通过各种途径实现淋巴细胞增殖所需的细胞外游离钙离子（Ca++）水平尚未得到详细研究。我们研究了凝集素促有丝分裂原（PHA）和钙离子载体（离子霉素）在不同细胞外Ca++浓度下诱导白细胞介素2受体、白细胞介素2（IL2）产生及增殖的能力。在PHA刺激的培养物中，将Ca++水平从正常的200微摩尔降至10微摩尔会部分抑制IL2受体表达、IL2产生及随后的增殖。在Ca++浓度为1微摩尔时，IL2活性和增殖均被消除，但仍可观察到部分IL2受体表达。在细胞外Ca++浓度低于100微摩尔的培养物中，离子霉素未诱导上述任何事件。当用有丝分裂原刺激外周血淋巴细胞（PBL）时，恢复培养基中的钙会使IL2受体表达、IL2活性及增殖达到正常水平。外源性镁可部分恢复PHA刺激培养物中的这些事件，但以离子霉素作为有丝分裂原时则无作用。这些数据表明，与PHA相比，离子霉素的刺激对细胞外Ca++水平的依赖性更强。细胞外钙在获得IL2受体后似乎也是必需的，因为在细胞外Ca++水平非常低时可观察到IL2受体表达，但无IL2活性或增殖，且在这些条件下IL2无法恢复增殖反应。数据还表明，PHA而非离子霉素可通过镁依赖性途径激活淋巴细胞，或者PHA对二价阳离子辅助因子的特异性较低。
