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Receptor Inhibiting Its Recruitment to the IL-4 Suppresses STAT6

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Receptor Inhibiting Its Recruitment to the IL-4 Suppresses STAT6 IFN-γ Suppresses STAT6 Phosphorylation by Inhibiting Its Recruitment to the IL-4 Receptor This information is current as Zan Huang, Junping Xin, John Coleman and Hua Huang of September 27, 2021. J Immunol 2005; 174:1332-1337; ; doi: 10.4049/jimmunol.174.3.1332 http://www.jimmunol.org/content/174/3/1332 Downloaded from References This article cites 38 articles, 23 of which you can access for free at: http://www.jimmunol.org/content/174/3/1332.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 27, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology IFN-␥ Suppresses STAT6 Phosphorylation by Inhibiting Its Recruitment to the IL-4 Receptor1 Zan Huang,* Junping Xin,† John Coleman,† and Hua Huang2*† Polarized Th1 cells show a stable phenotype: they become insensitive to IL-4 stimulation and lose the potential to produce IL-4. Previously, we reported that IFN-␥ played a critical role in stabilizing Th1 phenotype. However, the mechanism by which IFN-␥ stabilizes Th1 phenotype is not clear. In this study, we compared STAT6 phosphorylation in wild-type (WT) and IFN-␥ receptor knockout (IFNGR؊/؊) Th1 cells. We found a striking diminution of STAT6 phosphorylation in differentiated WT Th1 cells, but not in differentiated IFNGR؊/؊ Th1 cells. The impairment of STAT6 phosphorylation in differentiated WT Th1 cells was not due to a lack of IL-4R expression or phosphorylation. Jak1 and Jak3 expression and phosphorylation were comparable in both cell types. No differential expression of suppressor of cytokine signaling 1 (SOCS1), SOCS3, or SOCS5 was observed in the two cell Downloaded from types. In addition, Src homology 2-containing phosphatase mutation did not affect IL-4-induced STAT6 phosphorylation in differentiated Th1 cells derived from viable motheaten (mev/mev) mice. These results led us to focus on a novel mechanism. By using a pulldown assay, we observed that STAT6 in WT Th1 cells bound less effectively to the phosphorylated IL-4R/GST fusion protein than that in IFNGR؊/؊ Th1 cells. Our results suggest that IFN-␥ may suppress phosphorylation of STAT6 by inhibiting its recruitment to the IL-4R. The Journal of Immunology, 2005, 174: 1332–1337. http://www.jimmunol.org/ helper type 1 cells are central immune components in of GATA3 and c-maf expression that control Th2 polarization (17– combating invasion of intracellular pathogens. They help 21). Thus, the Jak-STAT6 pathway becomes a logical target to be T CD8ϩ T cells to become killer T cells and B cells to rendered insensitive to IL-4 stimulation. produce Abs through their cytokine production, such as IFN-␥, We previously showed that Th1 cells that lacked IFN-␥ or IL-2, TNF-␣, and TNF-␤ (lymph toxin). In contrast, uncontrolled IFN-␥ responsiveness retained the ability to respond to IL-4 (22), Th1 response can cause autoimmune disease (1, 2). Dysregulated suggesting that IFN-␥ plays an important role in Th1 cell com- Th1 cells found in autoimmune diseases display highly polarized mitment. Two classes of molecules, Src homology 2 (SH2)3 do- phenotype. Their cytokine-producing profiles remain unchanged main-containing protein tyrosine phosphatase and suppressor of by guest on September 27, 2021 even after exposure to Th2-inducing conditions. It is still unsolved cytokine signaling (SOCS), have been shown to inhibit IL-4-in- how Th1 cells become insensitive to Th2-inducing conditions. duced STAT6 phosphorylation in various cell types (23–26). SH2- Previously, we reported that committed Th1 cells were insensi- containing phosphatase (SHP-1) dephosphorylates STAT6 in B tive to Th2-inducing conditions; they exhibit strikingly diminished cells, macrophages, and fibroblast cells (27–29). SOCS1 inhibits STAT6 phosphorylation in response to IL-4 stimulation (3). IL-4 STAT6 phosphorylation in monocytes, liver cells, and B cells (30– is the major determinant in directing naive CD4ϩ T cells to dif- 32). SOCS5 was shown to suppress STAT6 phosphorylation in ferentiate into Th2 cells (4–7). It mediates its function by binding Th1 cells (33). Whether IFN-␥ can suppress STAT6 phosphory- and stimulating the IL-4R ␣-chain (8, 9). Ligand-bound IL-4R lation in committed CD4ϩ Th1 cells through the known classes of ␣-chain recruits common ␥-chain and its associated kinase Jak3 inhibitors is not clear. (10, 11). Jak3 and IL-4R ␣-chain-associated Jak1 then phosphor- In this study, we analyzed the role of known STAT6 phosphor- ylate each other and become activated (12–14). Activated Jak1 and ylation inhibitors in both wild-type (WT) and IFN-␥ receptor Jak3 phosphorylate the IL-4R on several tyrosine residues located knockout (IFNGRϪ/Ϫ) Th1 cells and we did not find evidence to in the C-terminal portion (15). The phosphorylated IL-4R serve as support that these known inhibitors mediated the inhibition of docking sites to recruit STAT6 as a substrate for activated Jak1 STAT6 phosphorylation. Rather, by using a newly developed pull- and Jak3 (16). Activation of STAT6 is essential for the induction down assay, we observed that STAT6 from WT Th1 cells bound less effectively to the phosphorylated IL-4R than that from IFNGRϪ/Ϫ Th1 cells. These results suggest that IFN-␥ mediates *Graduate Program in Molecular Biology and †Department of Cell Biology, Stritch inhibition of STAT6 phosphorylation through a novel mechanism. School of Medicine, Loyola University Chicago, Maywood, IL 60153 Received for publication March 25, 2004. Accepted for publication November 17, 2004. Materials and Methods The costs of publication of this article were defrayed in part by the payment of page Animals and cell cultures charges. This article must therefore be hereby marked advertisement in accordance ␣ ␤ with 18 U.S.C. Section 1734 solely to indicate this fact. Mice bearing transgenic TCR- and - chains specific for pigeon cyto- chrome c peptide 88–104 in association with the I-Ek class II molecule on 1 This study is supported by a grant from the Schweppe Foundation and a RO1 grant (A1 AI 48568) from the National Institutes of Health (to H.H.). 2 Address correspondence and reprint requests to Dr. Hua Huang, Department of Cell Biology, Stritch School of Medicine, Loyola University Chicago, Building 102, 3 Abbreviations used in this paper: SH2, Src homology 2; 4RC, IL-4R/GST fusion Room 5657, 2160 South First Avenue, Maywood, IL 60153. E-mail address: protein; 4RC-P, phosphorylated 4RC; SHP-1, SH2-containing phosphatase; SOCS, [email protected] suppressor of cytokine signaling; WT, wild type. Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 The Journal of Immunology 1333 C57BL/6 background (5CC7) were purchased from The Jackson Labora- added to the cultures, which were incubated at 30°C for another 1.5 h. The tory. The 5CC7 mice were crossed to IFN-␥ receptor-deficient mice on cells were collected and resuspended in1Lofmodified M9 medium (1ϫ C57BL/6 background (from The Jackson Laboratory) to generate 5CC7 M9 salts, 0.5% (w/v) casamino acids (Sigma-Aldrich A-2427), 0.1 mM ␥ Ϫ/Ϫ ␮ IFN- receptor-deficient mice (IFNGR ) on C57BL/6 background. Na- CaCl2, 0.2% glucose, 10 g/ml thiamine B1) in the presence of isopropy- ϩ ive CD4 T cells were prepared, as described elsewhere (22). These cells lthio-␤-D-galactoside, but no tryptophan. The cell suspension was incu- (1 ϫ 106) were stimulated with 1 ␮m of cytochrome c peptide (prepared by bated at 30°C for 1.5 h to induce the expression of the TrpE-v-Abl fusion Alpha Diagnostic International) and 5 ϫ 106 of I-Ek-expressing fibroblast protein. The 4RC- and v-Abl-expressing cells were harvested, resuspended cells (PI-39), irradiated with 2500 rad of gamma-ray, in 10 ml of complete in 20 ml of ice-cold lysis buffer (PBS, 50 mM EDTA, 1% Triton X-100, 1 RPMI 1640 medium supplemented with IL-2 (10 U/ml), IL-12 (10 ng/ml), mM DTT, 0.2 mM PMSF, 10 ␮g/ml pepstatin A, 10 ␮g/ml leupeptin, 10 anti-CD28 Ab (3 ␮g/ml, prepared from hybridoma 37.N.51.1, and provided ␮g/ml aprotinin), and sonicated in Sonic Dismembrator Model 60 (Fisher by J. Allison (University of California, Berkeley, CA)), and anti-IL-4 Ab Scientific) at 50% output for 2 min with 30-s intervals every minute. Cell (11B11; 10 ␮g/ml) for 3–11 days. The PI-39 cells were provided by R. lysates were incubated with 0.5 ml of glutathione Sepharose beads (Am- Germain (National Institutes of Health, Bethesda, MD). ersham Biosciences) at room temperature for 30 min. After extensive wash For preparing Th1 cells that were deficient in SHP-1 activity, C57BL/ with PBS, the beads were resuspended in 0.5 ml of lysis buffer and stored 6J-Hcphme-v/Hcphme-v (viable motheaten (mev/mev)) and littermate control at Ϫ70°C for later use. (ϩ/Ϫ) mice, maintained in The Jackson Laboratory and shipped to Loyola Medical Center animal facility 2 wk before experiments, were used. For priming of Th1 cells, primary stimulation of CD4ϩ T cells was conducted GST pulldown assay 6 ϩ 7 by culturing 10 CD4 T cells in the presence of 10 irradiated T-depleted The 4RC-P or unphosphorylated 4RC was expressed in E.
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