Klaus G G, Harnett M M
Division of Immunology, National Institute for Medical Research, Mill Hill, London, GB.
Eur J Immunol. 1990 Oct;20(10):2301-7. doi: 10.1002/eji.1830201020.
A well-known property of IL4 is its capacity to synergize with low concentrations of anti-immunoglobulin (Ig) antibodies to induce B cells to synthesize DNA. Cross-linking of surface Ig receptors stimulates phosphoinositide hydrolysis, with consequent production of two signals: the elevation of intracellular Ca2+ levels and activation of protein kinase C (PKC). Little is known about the second messengers utilized by interleukin (IL)4 receptors. In this study we have investigated the relative contributions of the two signals emanating from the ligation of surface Ig receptors to the synergistic activation of B cells by IL4. We show that IL4 plus carefully titrated concentrations of PKC-activating phorbol esters [such as phorbol 12,13-dibutyrate (PBu2)] induce cell cycle entry of virtually all murine B cells and substantial levels of DNA synthesis. Ca2+ ionophores, in contrast do not act as co-mitogens with IL4. However, a critical concentration of ionomycin further enhanced DNA synthesis induced by PBu2 plus IL4. Taken together, these results suggest that PKC activation alone is sufficient to synergize with IL4 in inducing B cells to enter cell cycle. However, the co-mitogenic effects of anti-Ig and IL4 are evidently also dependent on Ca2+ signals. This interpretation is supported by the findings that cyclosporin, which abrogates the activation of lymphocytes by Ca2(+)-dependent stimuli, inhibits B cell proliferation induced by anti-Ig plus IL4, but not the response to PBu2 plus IL4.
白细胞介素4（IL4）的一个广为人知的特性是，它能够与低浓度的抗免疫球蛋白（Ig）抗体协同作用，诱导B细胞合成DNA。表面Ig受体的交联刺激磷酸肌醇水解，从而产生两种信号：细胞内Ca2+水平升高和蛋白激酶C（PKC）激活。关于白细胞介素（IL）4受体所利用的第二信使知之甚少。在本研究中，我们调查了表面Ig受体连接产生的两种信号对IL4协同激活B细胞的相对贡献。我们发现，IL4加上经过仔细滴定浓度的PKC激活佛波酯[如佛波醇12,13 - 二丁酸酯（PBu2）]可诱导几乎所有小鼠B细胞进入细胞周期并进行大量的DNA合成。相比之下，Ca2+离子载体不能与IL4作为共刺激原起作用。然而，一定浓度的离子霉素可进一步增强PBu2加IL4诱导的DNA合成。综上所述，这些结果表明，单独的PKC激活足以与IL4协同作用，诱导B细胞进入细胞周期。然而，抗Ig和IL4的共刺激作用显然也依赖于Ca2+信号。环孢菌素可消除Ca2(+)-依赖性刺激对淋巴细胞的激活，它抑制抗Ig加IL4诱导的B细胞增殖，但不抑制对PBu2加IL4的反应，这一发现支持了上述解释。
