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Chain (V50) Regulates the Persistence of STAT6 Phosphorylation1
,
,
* Center for Vascular and Inflammatory Disease,
Program in Oncology, Marlene and Stewart Greenebaum Cancer Center, and
Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201;
Institute for Biomedical Sciences, George Washington University Medical Center, Washington, DC 20037; and
¶ Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232
Several commonly occurring polymorphisms in the IL-4R
have been associated with atopy in humans; the Q576R and the S503P polymorphisms reside in the cytoplasmic domain, whereas the I50 to V50 polymorphism resides in the extracellular domain of the IL-4R. The effects of these polymorphisms on signaling remain controversial. To determine the effect of the polymorphisms on IL-4 signaling in human cells, we stably transfected the human monocytic cell line U937 with murine IL-4R cDNA bearing the I or V at position 50 and the P503/R576 double mutant. Each form of the murine IL-4R mediated tyrosine phosphorylation of STAT6 in response to murine IL-4 treatment similar to the induction of tyrosine phosphorylation by human IL-4 signaling through the endogenous human IL-4R. After IL-4 removal, tyrosine-phosphorylated STAT6 rapidly decayed in cells expressing I50 or P503R576 murine IL-4R. In contrast, STAT6 remained significantly phosphorylated for several hours after murine IL-4 withdrawal in cells expressing the V50 polymorphism. This persistence in tyrosine-phosphorylated STAT6 was associated with persistence in CIS mRNA expression. Blocking IL-4 signaling during the decay phase using the JAK inhibitor AG490 or the anti-IL-4R Ab M1 abrogated the persistence of phosphorylated STAT6 observed in the V50-IL-4R-expressing cells. These results indicate that the V50 polymorphism promotes sustained STAT6 phosphorylation and that this process is mediated by continued engagement of IL-4R, suggesting enhanced responses of V50 IL-4R when IL-4 is limiting.
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1 This work was supported by Public Health Service Grants AI038985 (to A.D.K.) and T32HL007698 (to A.Q.F. and N.M.H.). A.Q.F. has submitted this work in partial fulfillment of the requirements for the Doctor of Philosophy degree, Immunology Program, Institute for Biomedical Sciences of the Columbian School of Arts and Sciences, The George Washington University, Washington, DC.
2 Address correspondence and reprint requests to Dr. Achsah D. Keegan, Center for Vascular and Inflammatory Diseases, University of Maryland, Baltimore, 800 West Baltimore Street, Baltimore, MD 21201. E-mail address: akeegan{at}som.umaryland.edu
3 Abbreviations used in this paper: PNGase F, peptide:N-glycosidase F; Endo H, endoglycosidase H.
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