Phosphatidylcholine-specific phospholipase C activity is necessary for the activation of STAT6.
It is well established that Janus kinase (JAK) tyrosine kinases play a key role in the activation of STAT6 by IL-4. In this study, we investigated additional molecules involved in this process. We previously found that IL-4 and TNF-alpha cooperate in the activation of STAT6 and NF-kappaB, suggesting that these transcription factors are regulated by common intracellular signaling pathways. To test this hypothesis, we analyzed the effect of known inhibitors of NF-kappaB on the activation of STAT6. We discovered that inhibitors of phosphatidylcholine-specific phospholipase C (PC-PLC), but not other lipases, blocked the activation of STAT6 by IL-4. The activation of PC-PLC seems to be an early event in IL-4 signaling, because its inhibition abrogated JAK activation and STAT6 tyrosine phosphorylation. Interestingly, we found that the effects of pervanadate and sodium orthovanadate on STAT6 activation correspond to their effect on PC-PLC. Thus, pervanadate by itself activated PC-PLC, JAK, and STAT6, whereas sodium orthovanadate suppressed PC-PLC, JAK, and STAT6 activation by IL-4. We further found that PC-PLC activation is necessary but not sufficient to promote STAT6 activation, and therefore, additional intracellular pathways regulated by IL-4 and pervanadate may collaborate with PC-PLC to signal STAT6 activation. It has been reported that IL-4 signals PC-PLC activation; in this study, we provide evidence that this phospholipase plays a key role in IL-4 signaling.
Zamorano
Jose
J
Unidad de Investigacion, Hospital San Pedro de Alcantara, Caceres, Spain. jzamorano@hspa.es
Rivas
Maria Dolores
MD
Garcia-Trinidad
Antonio
A
Qu
Cheng-Kui
CK
Keegan
Achsah D
AD
D000818:Animals; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006868:Hydrolysis / Q000187:drug effects; D015847:Interleukin-4 / Q000502:physiology; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D051379:Mice; D009636:Norbornanes; D010713:Phosphatidylcholines / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013379:Substrate Specificity / Q000187:drug effects / Q000276:immunology; D013859:Thiocarbamates; D013871:Thiones / Q000494:pharmacology; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D017968:Vanadium Compounds / Q000494:pharmacology
D001952:Bridged-Ring Compounds; D004791:Enzyme Inhibitors; D009636:Norbornanes; D010713:Phosphatidylcholines; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D013859:Thiocarbamates; D013871:Thiones; D015534:Trans-Activators; D017968:Vanadium Compounds; D015847:Interleukin-4; C046498:tricyclodecane-9-yl-xanthogenate; D011505:Protein-Tyrosine Kinases; C507905:Jak1 protein, mouse; C507935:Jak3 protein, mouse; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D010738:Type C Phospholipases; C105598:phosphatidylcholine-specific phospholipase C