Lacour M, Arrighi J F, Müller K M, Carlberg C, Saurat J H, Hauser C
Department of Dermatology, Hôpital Cantonal Universitaire de Genève, Switzerland.
Int Immunol. 1994 Sep;6(9):1333-43. doi: 10.1093/intimm/6.9.1333.
Seven days after activation with concanavalin A and irradiated spleen cells, murine CD4+ T cells were re-stimulated with ionomycin and phorbol 12-myristate 13-acetate (PMA). IL-2 and IL-4 were determined in the supernatant. When cholera toxin, forskolin together with phosphodiesterase inhibitors or dibutyryl-cAMP were added at the time of re-stimulation, a dose-dependent increase of IL-4 and IL-5 release was noted. IL-2 was down-regulated as reported before. The up-regulation of IL-4 and the down-regulation of IL-2 correlated with an increase of IL-4 mRNA and a decrease of IL-2 mRNA as determined by semi-quantitative reverse transcriptase polymerase chain reaction. Similar results were found with prostaglandin E2 using PMA and ionomycin or plate-bound anti-CD3 antibody as re-stimulants. These results suggest that, in activated CD4+ T cells, cAMP-elevating agents induce a switch of lymphokine production towards a Th2-like phenotype through regulation at the transcriptional level. This is supported by the fact that complex formation between a synthetic nuclear factor of activated T cells (NF-AT) binding site from the IL-2 promoter and nuclear extracts was decreased when cholera toxin was added to re-activated CD4+ T cells, suggesting that cholera toxin and cAMP down-regulate IL-2 expression via decreased NF-AT binding. Finally, since IL-4 has been reported to amplify IL-4 release from activated CD4+ T cells, the autoinduction of IL-4 may very well function via cAMP.
用伴刀豆球蛋白A激活并照射脾细胞7天后，用离子霉素和佛波酯（PMA）再次刺激小鼠CD4 + T细胞。测定上清液中的IL-2和IL-4。当在再次刺激时加入霍乱毒素、福斯可林以及磷酸二酯酶抑制剂或二丁酰环磷腺苷时，观察到IL-4和IL-5释放呈剂量依赖性增加。如之前报道的那样，IL-2被下调。通过半定量逆转录聚合酶链反应测定，IL-4的上调和IL-2的下调与IL-4 mRNA的增加和IL-2 mRNA的减少相关。使用PMA和离子霉素或板结合抗CD3抗体作为再次刺激剂时，前列腺素E2也得到了类似的结果。这些结果表明，在活化的CD4 + T细胞中，升高cAMP的试剂通过转录水平的调节诱导细胞因子产生向Th2样表型转变。这一观点得到以下事实的支持：当向再次活化的CD4 + T细胞中加入霍乱毒素时，来自IL-2启动子的活化T细胞合成核因子（NF-AT）结合位点与核提取物之间的复合物形成减少，这表明霍乱毒素和cAMP通过降低NF-AT结合来下调IL-2表达。最后，由于据报道IL-4可放大活化的CD4 + T细胞释放IL-4，IL-4的自诱导很可能通过cAMP发挥作用。
