Fedyk E R, Ripper J M, Brown D M, Phipps R P
Immunology and Thoracic Oncology Programs of the Cancer Center, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Mol Immunol. 1996 Jan;33(1):33-45. doi: 10.1016/0161-5890(95)00130-1.
The E-series prostaglandins (PGEs) are complex lipid regulators of B lymphocyte function. They inhibit the growth of certain B lymphoma lines. We report that heterogeneity with respect to PGE-induced growth inhibition correlates with the maturation state of the B cell lines. Specifically, the pre-B cell line 70Z/3 and the immature lymphoma CH31 are extremely sensitive to PGE2. To a lesser degree, other immature lymphomas (CH33, ECH408.1 and WEHI-231) are sensitive to PGE2. More mature lymphomas (BAL-17, CH12 and CH27) and fully differentiated myelomas (J558 and MOPC-315) are insensitive to PGE2. It is unknown what subtype of PGE receptor(s) (EPs) are expressed by B lymphocytes. It is also unknown if modulation of EP receptor expression could account for the differences in the sensitivity of these B cell lines to PGE2. To investigate these issues, reverse transcriptase polymerase chain reaction, Northern blot and DNA sequencing analyses were employed to obtain a definitive EP receptor subtype profile for these B cell lines, and for normal splenic B lymphocytes. Both normal and transformed B lymphocytes express mRNA encoding EP1, EP3beta and EP4 subtypes of PGE receptors. The B lineage cells do not express EP3alpha nor EP3gamma mRNA. The B cell lines are clonal, indicating that EP1, EP3beta and EP4 mRNA are coexpressed. Surprisingly, quantitative differences in basal EP1, EP3beta and EP4 expression were not observed between B cell lines despite their differing susceptibilities to PGE-induced growth inhibition. Conversely, the polyclonal activator LPS selectively upregulates EP4 mRNA expression in the mature B cell line CH12, but not in the LPS-sensitive pre-B cell line, 70Z/3. The activator LPS does not affect EP1 nor EP3beta mRNA expression. Treatment with dbcAMP, an analog of cAMP, mimics PGE-induced growth inhibition indicating that Gs-coupled EP2 and/or EP4 receptors mediate this inhibitory signal. Indeed, EP2 agonists mimic PGE2-induced growth inhibition unlike IP, EP1 and EP3-selective agonists. These data indicate that EP2 receptors are sufficient for mediating PGE-induced growth inhibition of susceptible B lineage cells.
E 系列前列腺素（PGEs）是 B 淋巴细胞功能的复杂脂质调节剂。它们抑制某些 B 淋巴瘤细胞系的生长。我们报告，PGE 诱导的生长抑制方面的异质性与 B 细胞系的成熟状态相关。具体而言，前 B 细胞系 70Z/3 和未成熟淋巴瘤 CH31 对 PGE2 极为敏感。其他未成熟淋巴瘤（CH33、ECH408.1 和 WEHI-231）对 PGE2 的敏感性较低。更成熟的淋巴瘤（BAL-17、CH12 和 CH27）以及完全分化的骨髓瘤（J558 和 MOPC-315）对 PGE2 不敏感。尚不清楚 B 淋巴细胞表达何种 PGE 受体（EP）亚型。也不清楚 EP 受体表达的调节是否可以解释这些 B 细胞系对 PGE2 敏感性的差异。为了研究这些问题，采用逆转录聚合酶链反应、Northern 印迹和 DNA 测序分析来获得这些 B 细胞系以及正常脾 B 淋巴细胞的明确 EP 受体亚型谱。正常和转化的 B 淋巴细胞均表达编码 PGE 受体 EP1、EP3β和 EP4 亚型的 mRNA。B 系细胞不表达 EP3α和 EP3γ mRNA。B 细胞系是克隆性的，表明 EP1、EP3β和 EP4 mRNA 共表达。令人惊讶的是，尽管 B 细胞系对 PGE 诱导的生长抑制敏感性不同，但未观察到它们之间基础 EP1、EP3β和 EP4 表达的定量差异。相反，多克隆激活剂脂多糖（LPS）选择性上调成熟 B 细胞系 CH12 中的 EP4 mRNA 表达，但在对 LPS 敏感的前 B 细胞系 70Z/3 中则不然。激活剂 LPS 不影响 EP1 和 EP3β mRNA 表达。用 cAMP 的类似物二丁酰环磷腺苷（dbcAMP）处理可模拟 PGE 诱导的生长抑制，表明与 Gs 偶联的 EP2 和/或 EP4 受体介导此抑制信号。实际上，与 IP、EP1 和 EP3 选择性激动剂不同，EP2 激动剂可模拟 PGE2 诱导的生长抑制。这些数据表明，EP2 受体足以介导 PGE 诱导的对易感 B 系细胞的生长抑制。
