Barrera S, Lai J, Fiocchi C, Roche J K
Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
J Cell Physiol. 1996 Jan;166(1):130-7. doi: 10.1002/(SICI)1097-4652(199601)166:1<130::AID-JCP15>3.0.CO;2-J.
Regulation of immune cell activation in lymphocyte-bearing human tissues is a pivotal host function, and metabolites of arachidonic acid (prostaglandin E2 in particular) have been reported to serve this function at non-mucosal sites. However, it is unknown whether prostaglandin E2 is immunoregulatory for the large lymphocyte population in the lamina propria of intestine; whether low (nM) concentrations of prostaglandin E2 modulate immune responses occurring there; and whether adjacent inflammation per se abrogates prostaglandin E2's regulatory effects. To address these issues, intestine-derived lymphocytes and T hybridoma cells were assessed, T cell activation was monitored by release of independently quantitated lymphokines, and dose-response studies were performed over an 8-log prostaglandin E2 concentration range. IL-3 release by normal intestinal lamina propria mononuclear cells was reduced (up to 78%) in a dose-dependent manner by prostaglandin E2, when present in as low a concentration as 10(-10) M. PGE2 also inhibited (by > or = 60%) mucosal T lymphocytes' ability to destabilize the barrier function of human epithelial monolayers. Further, with an intestine-derived T lymphocyte hybridoma cell line, a prostaglandin E2 dose-dependent reduction in IL-3 and IL-2 (90 and 95%, respectively) was found; this was true for both mitogen- and antigen-driven T cell lymphokine release. Concomitant [3H] thymidine uptake studies suggested this was not due to a prostaglandin E2-induced reduction in T cell proliferation or viability. In contrast, cells from chronically inflamed intestinal mucosa were substantially less sensitive to prostaglandin E2, e.g., high concentrations (10(-6) M) of prostaglandin E2 inhibited IL-3 release by only 41%. We conclude that prostaglandin E2 in nM concentrations is an important modulator of cytokine release from T lymphocytes derived from the gastrointestinal tract, and it may play a central role in regulation of lamina propria immunocyte populations residing there.
在含有淋巴细胞的人体组织中，免疫细胞激活的调节是一项关键的宿主功能，据报道，花生四烯酸的代谢产物（尤其是前列腺素E2）在非粘膜部位发挥此功能。然而，尚不清楚前列腺素E2对肠道固有层中的大量淋巴细胞是否具有免疫调节作用；低（纳摩尔）浓度的前列腺素E2是否能调节在那里发生的免疫反应；以及相邻炎症本身是否会消除前列腺素E2的调节作用。为了解决这些问题，对来源于肠道的淋巴细胞和T杂交瘤细胞进行了评估，通过独立定量的淋巴因子释放来监测T细胞激活，并在8个对数级的前列腺素E2浓度范围内进行剂量反应研究。当前列腺素E2以低至10^(-10) M的浓度存在时，正常肠道固有层单核细胞释放的IL-3以剂量依赖的方式减少（高达78%）。前列腺素E2还抑制（≥60%）粘膜T淋巴细胞破坏人上皮单层屏障功能的能力。此外，对于一种来源于肠道的T淋巴细胞杂交瘤细胞系，发现前列腺素E2剂量依赖性地降低IL-3和IL-2的释放（分别为90%和95%）；对于有丝分裂原和抗原驱动的T细胞淋巴因子释放均如此。同时进行的[3H]胸苷摄取研究表明，这不是由于前列腺素E2诱导的T细胞增殖或活力降低所致。相比之下，来自慢性炎症肠道粘膜的细胞对前列腺素E2的敏感性显著降低，例如，高浓度（10^(-6) M）的前列腺素E2仅抑制IL-3释放41%。我们得出结论，纳摩尔浓度的前列腺素E2是胃肠道来源的T淋巴细胞细胞因子释放的重要调节剂，它可能在调节驻留在那里的固有层免疫细胞群体中发挥核心作用。
