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Phosphatidylcholine-Specific Phospholipase C Activity Is Necessary for the Activation of STAT6 ¹

Jose Zamorano^2,*, Maria Dolores Rivas^*, Antonio Garcia-Trinidad^*, Cheng-Kui Qu and Achsah D. Keegan

^* Unidad de Investigacion, Hospital San Pedro de Alcantara, Caceres, Spain; and Departments of Hematopoiesis and Immunology, Holland Laboratory, American Red Cross, Rockville, MD 20855

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- cooperate in the activation of STAT6 and NF-B, 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-B 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.

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