BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Interferon-γ-mediated secretion of tryptophanyl-tRNA synthetases has a role in protection of human umbilical cord blood-derived mesenchymal stem cells against experimental colitis

  • Kang, Insung (Adult Stem Cell Research Center and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University) ;
  • Lee, Byung-Chul (Adult Stem Cell Research Center and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University) ;
  • Lee, Jin Young (Adult Stem Cell Research Center and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University) ;
  • Kim, Jae-Jun (Adult Stem Cell Research Center and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University) ;
  • Lee, Seung-Eun (Adult Stem Cell Research Center and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University) ;
  • Shin, Nari (Adult Stem Cell Research Center and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University) ;
  • Choi, Soon Won (Adult Stem Cell Research Center and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University) ;
  • Kang, Kyung-Sun (Adult Stem Cell Research Center and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University)
  • Received : 2018.06.22
  • Accepted : 2018.08.11
  • Published : 2019.05.31
Download PDF
⟨ Previous Next ⟩

Abstract

Mesenchymal stem cells (MSCs) are multipotent adult stem cells that present immunosuppressive effects in experimental and clinical trials targeting various rare diseases including inflammatory bowel disease (IBD). In addition, recent studies have reported tryptophanyl-tRNA synthetase (WRS) possesses uncanonical roles such as angiostatic and anti-inflammatory effects. However, little is known about the function of WRS in MSC-based therapy. In this study, we investigated if a novel factor, WRS, secreted from MSCs has a role in amelioration of IBD symptoms and determined a specific mechanism underlying MSC therapy. Experimental colitis was induced by administration of 3% DSS solution to 8-week-old mice and human umbilical cord blood-derived MSCs (hUCB-MSCs) were injected intraperitoneally. Secretion of WRS from hUCB-MSCs and direct effect of WRS on isolated $CD4^+$ T cells was determined via in vitro experiments and hUCB-MSCs showed significant therapeutic rescue against experimental colitis. Importantly, WRS level in serum of colitis induced mice decreased and recovered by administration of MSCs. Through in vitro examination, WRS expression of hUCB-MSCs increased when cells were treated with interferon-${\gamma}$ ($IFN-{\gamma}$). WRS was evaluated and revealed to have a role in inhibiting activated T cells by inducing apoptosis. In summary, $IFN-{\gamma}$-mediated secretion of WRS from MSCs has a role in suppressive effect on excessive inflammation and disease progression of IBD and brings new highlights in the immunomodulatory potency of hUCB-MSCs.

Keywords

References

  1. Bouguen G and Peyrin-Biroulet L (2011) Surgery for adult Crohn's disease: what is the actual risk? Gut 60, 1178-1181 https://doi.org/10.1136/gut.2010.234617
  2. Hanauer SB (2003) Crohn's disease: step up or top down therapy. Best Pract Res Clin Gastroenterol 17, 131-137 https://doi.org/10.1053/bega.2003.0361
  3. Zhang Z, Liu Z, Chen J et al (2018) Resveratrol induces autophagic apoptosis via the lysosomal cathepsin D pathway in human drug-resistant K562/ADM leukemia cells. Exp Ther Med 15, 3012-3019
  4. Maggini J, Mirkin G, Bognanni I et al (2010) Mouse bone marrow-derived mesenchymal stromal cells turn activated macrophages into a regulatory-like profile. PLoS One 5, e9252 https://doi.org/10.1371/journal.pone.0009252
  5. Ciccocioppo R, Cangemi GC, Kruzliak P et al (2015) Ex vivo immunosuppressive effects of mesenchymal stem cells on Crohn's disease mucosal T cells are largely dependent on indoleamine 2, 3-dioxygenase activity and cell-cell contact. Stem Cell Res Ther 6, 137 https://doi.org/10.1186/s13287-015-0122-1
  6. Vasandan AB, Jahnavi S, Shashank C, Prasad P, Kumar A and Prasanna SJ (2016) Human Mesenchymal stem cells program macrophage plasticity by altering their metabolic status via a PGE 2-dependent mechanism. Sci Rep 6, 38308 https://doi.org/10.1038/srep38308
  7. Kim S, You S and Hwang D (2011) Aminoacyl-tRNA synthetases and tumorigenesis: more than housekeeping. Nat Rev Cancer 11, 708 https://doi.org/10.1038/nrc3124
  8. Guo M and Schimmel P (2013) Essential nontranslational functions of tRNA synthetases. Nat Chem Biol 9, 145 https://doi.org/10.1038/nchembio.1158
  9. Wakasugi K, Slike BM, Hood J et al (2002) A human aminoacyl-tRNA synthetase as a regulator of angiogenesis. Proc Natl Acad Sci U S A 99, 173-177 https://doi.org/10.1073/pnas.012602099
  10. Ahn YH, Park S, Choi JJ et al (2017) Secreted tryptophanyl-tRNA synthetase as a primary defence system against infection. Nat Microbiol 2, 16191 https://doi.org/10.1038/nmicrobiol.2016.191
  11. Gonzalez-Rey E, Anderson P, Gonzalez MA, Rico L, Buscher D and Delgado M (2009) Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis. Gut 58, 929-939 https://doi.org/10.1136/gut.2008.168534
  12. Kim HS, Shin TH, Lee BC et al (2013) Human umbilical cord blood mesenchymal stem cells reduce colitis in mice by activating NOD2 signaling to COX2. Gastroenterology 145, 1392-1403 https://doi.org/10.1053/j.gastro.2013.08.033
  13. Fichtner-Feigl S, Strober W, Geissler EK and Schlitt HJ (2008) Cytokines mediating the induction of chronic colitis and colitis-associated fibrosis. Mucosal Immunol 1 Suppl 1, S24-27 https://doi.org/10.1038/mi.2008.41
  14. Park SG, Ewalt KL and Kim S (2005) Functional expansion of aminoacyl-tRNA synthetases and their interacting factors: new perspectives on housekeepers. Trends Biochem Sci 30, 569-574 https://doi.org/10.1016/j.tibs.2005.08.004
  15. Noh KT, Cho J, Chun SH et al (2015) Resveratrol regulates naive CD 8+ T-cell proliferation by upregulating IFNgamma-induced tryptophanyl-tRNA synthetase expression. BMB Rep 48, 283-288 https://doi.org/10.5483/BMBRep.2015.48.5.190
  16. Globig AM, Hennecke N, Martin B et al (2014) Comprehensive intestinal T helper cell profiling reveals specific accumulation of IFN-gamma+IL-17+coproducing CD4+ T cells in active inflammatory bowel disease. Inflamm Bowel Dis 20, 2321-2329 https://doi.org/10.1097/MIB.0000000000000210
  17. Park SR, Kim HJ, Yang SR, Park CH, Lee HY and Hong IS (2018) A novel endogenous damage signal, glycyl tRNA synthetase, activates multiple beneficial functions of mesenchymal stem cells. Cell Death Differ 25, 2023-2036 https://doi.org/10.1038/s41418-018-0099-2
  18. Yadav MC, Burudi EM, Alirezaei M et al (2007) IFNgamma-induced IDO and WRS expression in microglia is differentially regulated by IL-4. Glia 55, 1385-1396 https://doi.org/10.1002/glia.20544
  19. Fukui H, Hanaoka R and Kawahara A (2009) Noncanonical activity of seryl-tRNA synthetase is involved in vascular development. Circ Res 104, 1253-1259 https://doi.org/10.1161/CIRCRESAHA.108.191189
  20. Xu X, Shi Y, Zhang H-M et al (2012) Unique domain appended to vertebrate tRNA synthetase is essential for vascular development. Nat Commun 3, 681 https://doi.org/10.1038/ncomms1686
  21. Zhou Q, Kapoor M, Guo M et al (2010) Orthogonal use of a human tRNA synthetase active site to achieve multifunctionality. Nat Struct Mol Biol 17, 57 https://doi.org/10.1038/nsmb.1706
  22. Kang I, Lee BC, Choi SW et al (2018) Donor-dependent variation of human umbilical cord blood mesenchymal stem cells in response to hypoxic preconditioning and amelioration of limb ischemia. Exp Mol Med 50, 35 https://doi.org/10.1038/s12276-017-0014-9
  23. Kim DS, Jang IK, Lee MW et al (2018) Enhanced Immunosuppressive Properties of Human Mesenchymal Stem Cells Primed by Interferon-gamma. EBioMedicine 28, 261-273 https://doi.org/10.1016/j.ebiom.2018.01.002
  24. Wang S, Mao C, Zhao Z et al (2009) Increased TTS abrogates IDO-mediated CD4(+) T cells suppression in patients with Graves' disease. Endocrine 36, 119-125 https://doi.org/10.1007/s12020-009-9184-0
  25. Chen W (2011) IDO: more than an enzyme. Nat Immunol 12, 809 https://doi.org/10.1038/ni.2088
  26. Munn DH and Mellor AL (2013) Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol 34, 137-143 https://doi.org/10.1016/j.it.2012.10.001
  27. Miyanokoshi M, Yokosawa T and Wakasugi K (2018) Tryptophanyl-tRNA synthetase mediates high-affinity tryptophan uptake into human cells. J Biol Chem 293, 8428-8438 https://doi.org/10.1074/jbc.RA117.001247
  28. Lee BC, Kim HS, Shin TH et al (2016) PGE2 maintains self-renewal of human adult stem cells via EP2-mediated autocrine signaling and its production is regulated by cell-to-cell contact. Sci Rep 6, 26298 https://doi.org/10.1038/srep26298