Gukovskaya Anna S, Hosseini Saeed, Satoh Akihiko, Cheng Jason H, Nam Kyung J, Gukovsky Ilya, Pandol Stephen J
UCLA/VA Greater Los Angeles Healthcare System, West Los Angeles Center, Los Angeles, CA 90073, USA.
Am J Physiol Gastrointest Liver Physiol. 2004 Feb;286(2):G204-13. doi: 10.1152/ajpgi.00088.2003. Epub 2003 Sep 4.
Mechanisms of alcoholic pancreatitis remain unknown. Previously, we showed that ethanol feeding sensitizes rats to pancreatitis caused by CCK-8, at least in part, by augmenting activation of the proinflammatory transcription factor NF-kappaB. To elucidate the mechanism of sensitization, here we investigate the effect of ethanol on Ca(2+)- and PKC-mediated pathways of CCK-induced NF-kappaB activation using an in vitro system of rat pancreatic acini incubated with ethanol. Ethanol augmented CCK-8-induced activation of NF-kappaB, similar to our in vivo findings with ethanol-fed rats. In contrast, ethanol prevented NF-kappaB activation caused by thapsigargin, an agent that mobilizes intracellular Ca(2+) bypassing the receptor. Pharmacological analysis showed that NF-kappaB activation by thapsigargin but not by CCK-8 is mediated through the calcineurin pathway and that the inhibitory effect of ethanol on the thapsigargin-induced NF-kappaB activation could be through inhibiting this pathway. Ethanol augmented NF-kappaB activation induced by the phorbol ester PMA, a direct activator of PKC. Inhibitory analysis demonstrated that Ca(2+)-independent (novel and/or atypical) PKC isoforms are involved in NF-kappaB activation induced by both CCK-8 and PMA in cells treated and not treated with ethanol. The results indicate that ethanol differentially affects the Ca(2+)/calcineurin- and PKC-mediated pathways of NF-kappaB activation in pancreatic acinar cells. These effects may play a role in the ability of ethanol to sensitize pancreas to the inflammatory response and pancreatitis.
酒精性胰腺炎的发病机制尚不清楚。此前，我们发现，喂食乙醇会使大鼠对由胆囊收缩素-8（CCK-8）引起的胰腺炎敏感，至少部分原因是增强了促炎转录因子核因子κB（NF-κB）的激活。为阐明这种致敏机制，我们在此使用与乙醇孵育的大鼠胰腺腺泡体外系统，研究乙醇对CCK诱导的NF-κB激活的钙（Ca2+）和蛋白激酶C（PKC）介导途径的影响。乙醇增强了CCK-8诱导的NF-κB激活，这与我们在喂食乙醇的大鼠体内的发现相似。相比之下，乙醇可阻止由毒胡萝卜素引起的NF-κB激活，毒胡萝卜素是一种绕过受体动员细胞内Ca2+的试剂。药理学分析表明，毒胡萝卜素而非CCK-8诱导的NF-κB激活是通过钙调神经磷酸酶途径介导的，乙醇对毒胡萝卜素诱导的NF-κB激活的抑制作用可能是通过抑制该途径。乙醇增强了佛波酯PMA（PKC的直接激活剂）诱导的NF-κB激活。抑制分析表明，在未用乙醇处理和用乙醇处理的细胞中，不依赖Ca2+的（新型和/或非典型）PKC同工型均参与CCK-8和PMA诱导的NF-κB激活。结果表明，乙醇对胰腺腺泡细胞中NF-κB激活的Ca2+/钙调神经磷酸酶和PKC介导途径有不同影响。这些影响可能在乙醇使胰腺对炎症反应和胰腺炎敏感的能力中起作用。
