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Monophosphate/Protein Kinase ′ Adenosine 5 Calcitonin Gene-R Calcitonin Gene-Related Peptide and Cyclic Adenosine 5 ′-Monophosphate/Protein Kinase A Pathway Promote IL-9 Production in Th9 Differentiation Process This information is current as of September 28, 2021. Norihisa Mikami, Yayoi Miyagi, Kaori Sueda, Miku Takatsuji, So-ichiro Fukada, Hiroshi Yamamoto and Kazutake Tsujikawa J Immunol 2013; 190:4046-4055; Prepublished online 15 March 2013; Downloaded from doi: 10.4049/jimmunol.1203102 http://www.jimmunol.org/content/190/8/4046 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2013/03/15/jimmunol.120310 Material 2.DC1 References This article cites 56 articles, 18 of which you can access for free at: http://www.jimmunol.org/content/190/8/4046.full#ref-list-1 Why The JI? Submit online. by guest on September 28, 2021 • 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 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 © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Calcitonin Gene-Related Peptide and Cyclic Adenosine 59-Monophosphate/Protein Kinase A Pathway Promote IL-9 Production in Th9 Differentiation Process Norihisa Mikami, Yayoi Miyagi, Kaori Sueda, Miku Takatsuji, So-ichiro Fukada, Hiroshi Yamamoto, and Kazutake Tsujikawa Th9 cells are a novel Th cell subset that produces IL-9 and is involved in type I hypersensitivity such as airway inflammation. Although its critical roles in asthma have attracted interest, the physiological regulatory mechanisms of Th9 cell differentiation and function are largely unknown. Asthma is easily affected by psychological factors. Therefore, we investigated one of the phys- iological mediators derived from the nervous system, calcitonin gene-related peptide (CGRP), in asthma and Th9 cells because CGRP and activation of the cAMP/protein kinase A (PKA) pathway by CGRP are known to be important regulators in several Downloaded from immune responses and allergic diseases. In this study, we demonstrated that the CGRP/cAMP/PKA pathway promotes IL-9 pro- duction via NFATc2 activation by PKA-dependent glycogen synthase kinase-3b inactivation. Moreover, CGRP also induces the expression of PU.1, a critical transcriptional factor in Th9 cells, which depends on PKA, but not NFATc2. Additionally, we demonstrated the physiological importance of CGRP in IL-9 production and Th9 differentiation using an OVA-induced airway inflammation model and T cell–specific CGRP receptor-deficient mice. The present study revealed a novel regulatory mechanism comprising G protein–coupled receptor ligands and nervous system-derived substances in Th9 cell differentiation and type I http://www.jimmunol.org/ hypersensitivity. The Journal of Immunology, 2013, 190: 4046–4055. D4+ Th cells play central roles in acquired immunity. Th fluorobenzene. In contrast, Th2 cells produce IL-4, IL-5, and IL- cells can be divided into several subsets, including Th1, 13, which drive many allergic diseases, such as atopic dermatitis. C Th2, Th17, and regulatory T cells. These subsets dif- Recently,anewThcellsubsetthatsecretesmainlyIL-9was ferentiate themselves from naive T cells under specific cytokine identified and named the Th9 cell (5, 6). Th9 cells differentiate conditions during the stimulation by APC. Each Th cell differ- from naive Th cells in the presence of both TGF-b and IL-4, or entiation is regulated by a specific transcriptional factor. It is from Th2 cells in the presence of TGF-b (6). IL-9 influences known that T-bet, GATA3, and RORgt are master transcriptional many cell types, including T cells, B cells, mast cells, eosino- by guest on September 28, 2021 factors for Th1, Th2, and Th17 cell differentiation, respectively phils, lung epithelial cells, and hematopoietic progenitors (7–10). (1–3). Regulatory T cells also require stable expression of the The essential roles of IL-9 in the pathogenic progression of type I transcriptional factor Foxp3 for their development and suppressor hypersensitivity have been demonstrated using IL-9–transgenic phenotype (4). In addition to the obligatory role in acquired im- mice and IL-9–deficient mice. IL-9–transgenic mice exhibit ac- munity, Th cells contribute to induction of a number of immune celerated hypersensitivity, and the condition was suppressed in diseases. Th1 cells mediate type IV–delayed allergies such as IL-9–deficient mice (11, 12). Although type I hypersensitivity contact dermatitis elicited by trinitrochrolobenzene or dinitro- had been considered a Th2 cytokine (IL-4, IL-5, and IL-13)- mediated reaction, recent findings showed that the blockade of IL-4 signaling had little effect on human asthma, and currently Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceuti- cal Sciences, Osaka University, Osaka 565-0871, Japan IL-9 is attracting attention as a new therapeutic target of type I Received for publication November 9, 2012. Accepted for publication February 19, hypersensitivity (13). 2013. PU.1 is reported to be an important transcriptional regulator of This work was supported by Grant-in-Aid for Scientific Research 22590062 from the Th9 cell differentiation (14). In addition, a few studies indicated Ministry of Education, Culture, Sports, Science, and Technology of Japan; a grant that other factors, such as NF-kB, NFATc2, and IFN regulatory from the Japan Chemical Industry Association Long-Range Research Initiative; a grant from the Osaka Foundation for Promotion of Clinical Immunology; and factor 4 (IRF-4), regulate IL-9 production in Th9 cells (15–17). a grant-in-aid for scientific research from the Japan Society for the Promotion of However, the molecular mechanisms and physiological regulators Science fellows. of Th9 differentiation are largely unknown; thus, it is extremely Address correspondence and reprint requests to Dr. So-ichiro Fukada, Laboratory of important to investigate how Th9 cell differentiation is regulated Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan. E-mail address: in the clinical condition of type I hypersensitivity. [email protected] There are many lines of evidence that an elevated cAMP level The online version of this article contains supplemental material. in immune cells affects several immune responses, such as cyto- Abbreviations used in this article: 6-bnz-cAMP, N6-benzoyl-cAMP; CGRP, calcito- kine production, cell proliferation, apoptosis, chemotaxis, and phago- nin gene-related peptide; ChIP, chromatin immunoprecipitation; 8-CPT-cAMP, 8-(4- cytosis (18–22). Generally, the intracellular cAMP level increases chlorophenylthio)-29-O-methyl-cAMP; EPAC, exchange factor directly activated by cAMP; GPCR, G protein–coupled receptor; GSK, glycogen synthase kinase; IRF-4, when the ligand binds to its G protein–coupled receptor (GPCR) IFN regulatory factor 4; PACAP, pituitary adenylate cyclase–activating polypeptide; and adenylate cyclase is activated. PKA, protein kinase A; RAMP1, receptor activity modifying protein 1; VIP, vaso- There are many GPCR ligands in neurotransmitters, and it is active intestinal peptide. well known that the immune system and allergic responses are Copyright Ó 2013 by The American Association of Immunologists, Inc. 0022-1767/13/$16.00 affected by the nervous system. In fact, the impact of psychological www.jimmunol.org/cgi/doi/10.4049/jimmunol.1203102 The Journal of Immunology 4047 factors on the pathogenesis of asthma has been well studied (23). (Osaka, Japan), and bCGRP was purchased from Phoenix Pharmaceuticals Calcitonin gene-related peptide (CGRP) is a 37-aa neuropeptide (Burlingame, CA). Human rTGF-b1 and mouse rIL-4 were purchased that is released from sensory neurons by several types of stimula- from PeproTech (Rocky Hill, NJ). Dibutyryl cAMP and lithium chloride were bought from Wako Pure Chemical Industries (Osaka, Japan). N6- tion, such as protons, heat, chemical, and psychological events, and benzoyl-cAMP (6-bnz-cAMP), 8-(4-chlorophenylthio)-29-O-methyl- increases the intracellular cAMP level through its specific recep- cAMP (8-CPT-cAMP), and GSK-3b inhibitor VII came from Calbio- tors. We hypothesized that CGRP is a potent Th9 regulator because chem (San Diego, CA). PGE2 and the PKA inhibitors (H89 and KT5720) its expression is increased in asthma (24, 25), and CGRP also has were purchased from Sigma-Aldrich (St. Louis, MO). PGD2 was pur- chased from Cayman Chemical (Ann Arbor, MI). LPS-free OVA was potent regulatory effects on Th cell differentiation (26–28). The bought from Seikagaku (Tokyo, Japan). CGRP receptor is a compound of receptor activity modifying pro- tein 1 (RAMP1), which has the binding site of CGRP, and calci- Isolation and differentiation of naive T cells tonin receptor-like receptor, which is coupled with Ga proteins. CD4+CD252CD44lowCD62L+ naive Th cells, which purified from spleen CGRP receptors are expressed not only in nerve cells, but also in cells by using a FACS Aria II (BD Biosciences, San Diego, CA), had various types of immune cells, and many effects of CGRP on im- purity .99% (data not shown). The purified naive Th cells were stimulated mune functions are reported in addition to Th cell differentiation. with plate-bound anti-CD3 mAb (2C11) and soluble anti-CD28 mAb (PV- 1; Beckman Coulter) for 48 h. The culture medium was supplemented with For instance, CGRP inhibits T cell proliferation, Ag presentation, rIL-4 (10 ng/ml) or rIL-4 (10 ng/ml) plus TGF-b (5 ng/ml) for Th2 or Th9 and Ab secretion (29–31).
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