IL 22 Is Expressed by the Invasive Trophoblast of the Equine Equus caballus Chorionic Girdle This information is current as of April 24 2012 Subscriptions Permissions Email Alerts J Immunol 2012 188 4181 4187 Prepublished online 4 April 2012 doi 10 4049 jimmunol 1103509 http www jimmunol org content 188 9 4181 This article cites 52 articles 17 of which can be accessed free at http www jimmunol org content 188 9 4181 full html ref list 1 Information about subscribing to The Journal of Immunology is online at http www jimmunol org subscriptions Submit copyright permission requests at http www aai org ji copyright html Receive free email alerts when new articles cite this article Sign up at http www jimmunol org etoc subscriptions shtml The Journal of Immunology is published twice each month by The American Association of Immunologists Inc 9650 Rockville Pike Bethesda MD 20814 3994 Copyright 2012 by The American Association of Immunologists Inc All rights reserved Print ISSN 0022 1767 Online ISSN 1550 6606 Downloaded from www jimmunol org on April 24 2012 References Margaret M Brosnahan Donald C Miller Mackenzie Adams and Douglas F Antczak The Journal of Immunology IL 22 Is Expressed by the Invasive Trophoblast of the Equine Equus caballus Chorionic Girdle Margaret M Brosnahan Donald C Miller Mackenzie Adams and Douglas F Antczak T he mechanisms that enable feto placental tissues to evade destruction by the maternal immune system are a longstanding focus of scientific investigation In the decades since Medawar proposed the fetus as allograft model reviewed by Billington 1 research has implicated a complex communication between trophoblast maternal immune cells and endometrium Examples include production of IL 4 and IL 10 2 HLA G IDO 3 and complement regulatory proteins 4 by trophoblast expression of RCAS1 by endometrium 3 and FOXP3 regulatory T cells at sites of trophoblast invasion 5 Migration and endometrial invasion are attributes of trophoblast cells in many species with the binucleate equine chorionic girdle CG cells being one example of this invasive phenotype 6 Deep invasion of trophoblast is thought to have played a role in human evolution by facilitating development of the human brain yet this process also brings increased risk of immune related placental dysfunction and diseases such as pre eclampsia 7 Some immunomodulatory molecules e g galectins are proposed to have evolved in tandem with specific forms of placentation 7 8 Trophoblast cells may also be novel sources of molecules proBaker Institute for Animal Health College of Veterinary Medicine Cornell University Ithaca NY 14853 Received for publication December 6 2011 Accepted for publication February 19 2012 This work was supported by National Institutes of Health Grants R01 HD049545 T32 RR007059 and K08 HD065914 and the Zweig Memorial Fund D F A is an investigator of the Dorothy Russell Havemeyer Foundation The microarray data presented in this article have been submitted to the Gene Expression Omnibus http www ncbi nlm nih gov geo under accession number GSE35743 Address correspondence and reprint requests to Prof Douglas F Antczak Baker Institute for Animal Health College of Veterinary Medicine Cornell University Ithaca NY 14853 E mail address dfa1 cornell edu Abbreviations used in this article CG chorionic girdle qRT PCR quantitative RTPCR Copyright 2012 by The American Association of Immunologists Inc 0022 1767 12 16 00 www jimmunol org cgi doi 10 4049 jimmunol 1103509 duced by immune cells in adult organisms as in the production of macrophage migration inhibitory factor by human villous cytotrophoblasts 9 and murine trophoblast giant cells 10 Using gene expression array analysis comparing invasive and noninvasive equine trophoblast we identified novel production of the immunomodulatory cytokine IL 22 by CG cells just prior to their migration through the endometrium to form the binucleate chorionic gonadotropin producing endometrial cups 11 IL 22 is a member of the IL 10 family of cytokines 12 and is involved in mucosal immunity and the maintenance and repair of epithelia 13 16 Since its first description in 2000 in human and mouse T cells 17 18 IL 22 has been documented exclusively in immune cells including Th subsets Th17 Th22 NK cells and bovine gd T cells 13 19 22 IL 22 acts upon a heterodimeric receptor composed of its primary target IL 22R1 and IL 10R2 23 This receptor is expressed on epithelial surfaces including respiratory 24 and digestive tracts and skin 25 Binding of IL 22R1 by IL 22 activates transcription factors STAT3 STAT1 or STAT5 26 and regulates genes associated with innate immunity 27 and cellular differentiation migration and survival 28 29 A second receptor IL22R2 is a soluble binding protein thought to block downstream functions of IL 22 30 31 This study presents our initial microarray finding of IL 22 expression by CG cells substantiates and expands upon this using quantitative RT PCR qRT PCR and bioinformatics and identifies potential targets expressing IL 22R1 mRNA Materials and Methods Animals Mares of various breeds ages and parity were bred by artificial insemination to thoroughbred stallions using techniques previously described 32 All horses were owned by the Cornell Center for Equine Genetics and maintained in a herd setting Procedures were performed in accordance with an animal care and use protocol approved by the Institutional Animal Care and Use Committee of Cornell University Downloaded from www jimmunol org on April 24 2012 The invasive trophoblast cells of the equine placenta migrate into the endometrium to form endometrial cups dense accumulations of trophoblast cells that produce equine chorionic gonadotropin between days 40 and 120 of normal pregnancy The mechanisms by which the trophoblast cells invade the endometrium while evading maternal immune destruction are poorly defined A gene expression microarray analysis performed on placental tissues obtained at day 34 of gestation revealed a 900 fold upregulation of mRNA encoding the cytokine IL 22 in chorionic girdle relative to noninvasive chorion Quantitative RT PCR assays were used to verify high expression of IL 22 in chorionic girdle Additional quantitative RT PCR analysis showed a striking increase in IL 22 mRNA expression in chorionic girdle from days 32 to 35 and an absence of IL 22 expression in other conceptus tissues Bioinformatic analysis and cDNA sequencing confirmed the predicted length of horse IL 22 which
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