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Transcription and Mrna Stabilization Multiple Pathways to Induce IL-4

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Transcription and Mrna Stabilization Multiple Pathways to Induce IL-4 Elevating Calcium in Th2 Cells Activates Multiple Pathways to Induce IL-4 Transcription and mRNA Stabilization This information is current as Liying Guo, Joseph F. Urban, Jinfang Zhu and William E. of October 2, 2021. Paul J Immunol 2008; 181:3984-3993; ; doi: 10.4049/jimmunol.181.6.3984 http://www.jimmunol.org/content/181/6/3984 Downloaded from References This article cites 51 articles, 23 of which you can access for free at: http://www.jimmunol.org/content/181/6/3984.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • 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 October 2, 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 © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Elevating Calcium in Th2 Cells Activates Multiple Pathways to Induce IL-4 Transcription and mRNA Stabilization1 Liying Guo,2* Joseph F. Urban,† Jinfang Zhu,* and William E. Paul* PMA and ionomycin cause T cell cytokine production. We report that ionomycin alone induces IL-4 and IFN-␥, but not IL-2, from in vivo- and in vitro-generated murine Th2 and Th1 cells. Ionomycin-induced cytokine production requires NFAT, p38, and calmodulin-dependent kinase IV (CaMKIV). Ionomycin induces p38 phosphorylation through a calcium-dependent, cyclosporine A-inhibitable pathway. Knocking down ASK1 inhibits ionomycin-induced p38 phosphorylation and IL-4 production. Ionomycin also activates CaMKIV, which, together with p38, induces AP-1. Cooperation between AP-1 and NFAT leads to Il4 gene tran- scription. p38 also regulates IL-4 production by mRNA stabilization. TCR stimulation also phosphorylates p38, partially through the calcium-dependent pathway; activated p38 is required for optimal IL-4 and IFN-␥. The Journal of Immunology, 2008, 181: 3984–3993. Downloaded from ptimal activation of T cells requires engagement of the radiation, heat shock, and osmotic shock, as well as by proinflam- TCR-CD3 complex and of costimulatory molecules matory cytokines, such as TNF-␣ and IL-1. Ligation of the TCR whose ligands are expressed on APCs (1). The binding also activates p38. TCR stimulation triggers small GTP-binding O 2ϩ of Ag/MHC complexes to the TCR elevates intracellular Ca proteins such as Ras, Rac-1, and Cdc42, leading to the activation 2ϩ 3 ␪ ␪ 180 concentration ([Ca ]i) and activates protein kinase C (PKC ). of MAPK cascades (7, 8). p38 is dually phosphorylated at Thr 182 The combination of a calcium ionophore (e.g., ionomycin) and and Tyr in a highly conserved motif in the p38 activation loop. http://www.jimmunol.org/ phorbol ester tumor promoters (e.g., PMA), which bypass TCR Salvador and colleagues reported an alternative p38 activation signals, results in T cell activation (2) and production of a series of pathway in T cells, in which ZAP70 phosphorylates p38␣ on cytokines, including IL-2, IL-4, and IFN-␥. Tyr323, leading to autophosphorylation of the Thr and Tyr in the 2ϩ Elevation of [Ca ]i is an essential event following TCR stim- activation loop and to “self-activation” (9). TCR stimulation thus ulation (3). Imaging studies reveal that TCR stimulation causes results in induction of both the classic MAPK cascade and this 2ϩ sustained elevation in [Ca ]i over a period of 1–2 h. Such sus- alternative p38 inhibitor-sensitive self-activation pathway; the rel- tained signaling allows dephosphorylated NFAT, a key transcrip- ative contributions of the two pathways and their physiological tional regulator of cytokine genes, to be maintained in the nucleus functions remain to be determined. (4). The cooperative action of NFAT and AP-1 is generally The importance of p38 activity to cytokine production is still by guest on October 2, 2021 thought to be necessary for full cytokine transcription (5). controversial. Herein we report that ionomycin alone induces IL-4 PKC␪ is a signal regulator of several T cell activation pathways and IFN-␥ production from in vivo- and in vitro-generated Th2 (6). The MAP kinases ERK, JNK, and p38 are among the targets and Th1 cells, in contrast to IL-2, for which both PMA and iono- of PKC␪. The ERK and JNK pathways are involved in IL-2 pro- mycin are essential for production. The production of IL-4 requires 2ϩ duction, predominantly through activation of AP-1 (7). However, elevation of [Ca ]i, NFAT dephosphorylation, and activation of relatively little is known about the role of p38 MAPK in cytokine p38 and CaMKIV. Phospho-p38 generated through elevation of 2ϩ induction. [Ca ]i plays a crucial role in ionomycin-induced IL-4 production Four p38 MAPK isoforms have been characterized: p38␣, p38␤, by promoting Il4 gene transcription and stabilizing its mRNA. Fur- p38␥, and p38␦. CD4 T cells predominantly express p38␣ and thermore, we show that phospho-p38 is essential for optimal IL-4 p38␦ (8). p38 can be activated by multiple stressors, such as UV production induced through TCR stimulation. *Laboratory of Immunology, National Institute of Allergy and Infectious Dis- Materials and Methods eases, National Institutes of Health, Bethesda, MD 20892; and †Nutrient Require- Mice and cell culture ments & Functions Laboratory, Beltsville Human Nutrition Research Center, Ag- ricultural Research Service, United States Department of Agriculture, Beltsville, Cells from C57BL/6 mice infected with Schistosoma mansoni cercariae for MD 20705 8 wk and splenocytes from C57BL/6 mice infected with Toxoplasma gon- Received for publication April 7, 2008. Accepted for publication July 11, 2008. dii for 10 days were kindly provided by Dr. Dragana Jankovic of the Na- tional Institute of Allergy and Infectious Diseases (10, 11). C57BL/6 mice The costs of publication of this article were defrayed in part by the payment of page were inoculated with third-stage Heligmosomoides polygyrus per os, and charges. This article must therefore be hereby marked advertisement in accordance spleens were isolated 14 days later, as previously described (12). with 18 U.S.C. Section 1734 solely to indicate this fact. CD4 T cells were purified from 5C.C7 transgenic Rag2Ϫ/Ϫ mice by 1 This research was supported by the Intramural Research Program of the National negative selection. Cells were cultured under Th1 and TH2 conditions as Institutes of Health, National Institute of Allergy and Infectious Diseases. described before (13). CD4 T cells were purified from Il4/Gfp heterozy- 2 Address correspondence and reprint requests to Dr. Liying Guo, Laboratory of Im- gous mice by negative selection. The cells were primed with APC, anti- munology, National Institute of Allergy and Infectious Diseases, National Institutes of CD3 (3 ␮g/ml), and anti-CD28 (3 ␮g/ml) under Th2 conditions. Health, Building 10, Room 11N322, 10 Center Drive–MSC 1892, Bethesda, MD 20892-1892. E-mail address: [email protected] Intracellular staining 3 2ϩ 2ϩ Abbreviations used in this paper: [Ca ]i, intracellular Ca concentration; ARE, adenylate/uridylate-rich elements; CsA, cyclosporine A; LN, lymph node; MFI, mean In vitro differentiated Th1 and Th2 cells were rechallenged under different fluorescence intensity; PB, plate-bound; PKC␪, protein kinase C␪; qPCR, quantitative conditions for 4 h, in the presence of monensin, to check cytokine produc- PCR; shRNA, small hairpin RNA; TG, thapsigargin; UTR, untranslated region. tion. The conditions used to rechallenge the cells were: APC ϩ peptide, www.jimmunol.org The Journal of Immunology 3985 FIGURE 1. Ionomycin induces substantial IL-4 and IFN-␥ production, but not IL-2, from in vivo- and in vitro-generated Th1 and Th2 cells. A, Mesenteric LNs were isolated from C57BL/6 mice 8 wk after S. mansoni infection and cells were stimulated for 4 h. IL-4 production by CD44brightCD4 T cells was measured by intracellular staining. B, Splenocytes were isolated from C57BL/6 mice 2 wk after H. polygyrus infection. IL-4 (upper panel) and Downloaded from IL-2 (lower panel) production by CD44brightCD4 T cells. C and D, Two round-primed Th1 or Th2 cells were stimulated under different conditions; percentage of cytokine-producing cells and MFI of the cytokine-producing cells are shown. IL-4 production (C, upper panel) and IL-2 (D, upper panel) in Th2 cells; IFN-␥ production (C, lower panel) and IL-2 (D, lower panel) in Th1 cells. The in vivo experiments were conducted twice and the in vitro experiments multiple times. cognate cytochrome C peptide (1 ␮M)-loaded APC; anti-CD3/CD28, tion, cells were maintained in medium containing IL-2 and puromycin (5 http://www.jimmunol.org/ plate-bound (PB) anti-CD3 (3 ␮g/ml) and anti-CD28 (3 ␮g/ml); PϩI, PMA ␮g/ml) (Sigma-Aldrich). Another 2 days later, puromycin-resistant cells (10 ng/ml) and ionomycin (1 ␮M), and ionomycin (1 ␮M) alone. were purified by cell sorting. Harvested cells were fixed with 4% paraformadehyde, washed with 0.1% BSA-containing PBS, and stored at 4°C. For staining, cells were Retroviral infection incubated with permeabilization buffer (PBS supplemented with 0.1% GFP-Cre viral supernatant was prepared as described before (14). Splenic BSA/0.1% Triton X-100) and various Abs for 20 min. All Abs were pur- CD4 T cells were purified from mice homozygous for a “floxed” TAK1 chased from BD Pharmingen.
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