Histochemistry and Cell Biology

, Volume 138, Issue 3, pp 397–406 | Cite as

Fatty acid-binding protein 4 (FABP4) and FABP5 modulate cytokine production in the mouse thymic epithelial cells

  • Yasuhiro Adachi
  • Sumie Hiramatsu
  • Nobuko Tokuda
  • Kazem Sharifi
  • Majid Ebrahimi
  • Ariful Islam
  • Yoshiteru Kagawa
  • Linda Koshy Vaidyan
  • Tomoo Sawada
  • Kimikazu Hamano
  • Yuji Owada
Original Paper


Thymic stromal cells, including cortical thymic epithelial cells (cTEC) produce many humoral factors, such as cytokines and eicosanoids to modulate thymocyte homeostasis, thereby regulating the peripheral immune responses. In this study, we identified fatty acid-binding protein (FABP4), an intracellular fatty acid chaperone, in the mouse thymus, and examined its role in the control of cytokine production in comparison with FABP5. By immunofluorescent staining, FABP4+ cells enclosing the thymocytes were scattered throughout the thymic cortex with a spatial difference from the FABP5+ cell that were distributed widely throughout the cTEC. The FABP4+ cells were immunopositive for MHC class II, NLDC145 and cytokeratin 8, and were identified as part of cTEC. The FABP4+ cells were identified as thymic nurse cells (TNC), a subpopulation of cTEC, by their active phagocytosis of apoptotic thymocytes. Furthermore, FABP4 expression was confirmed in the isolated TNC at the gene and protein levels. To explore the function of FABP in TNC, TSt-4/DLL1 cells stably expressing either FABP4 or FABP5 were established and the gene expressions of various cytokines were examined. The gene expression of interleukin (IL)-7 and IL-18 was increased both in FABP4 and FABP5 over-expressing cells compared with controls, and moreover, the increase in their expressions by adding of stearic acids was significantly enhanced in the FABP4 over-expressing cells. These data suggest that both FABPs are involved in the maintenance of T lymphocyte homeostasis through the modulation of cytokine production, which is possibly regulated by cellular fatty acid-mediated signaling in TEC, including TNC.


Fatty acid-binding protein Thymus Thymic epithelial cells Thymic nurse cells IL-7 IL-18 

Supplementary material

418_2012_963_MOESM1_ESM.doc (41 kb)
Supplementary material 1 (DOC 41 kb)
418_2012_963_MOESM2_ESM.doc (31 kb)
Supplementary material 2 (DOC 31 kb)
418_2012_963_MOESM3_ESM.doc (30 kb)
Supplementary material 3 (DOC 29 kb)


  1. Abdelwahab SA, Owada Y, Kitanaka N, Adida A, Sakagami H, Ono M, Watanabe M, Spener F, Kondo H (2007) Enhanced expression of adipocyte-type fatty acid binding protein in murine lymphocytes in response to dexamethasone treatment. Mol Cell Biochem 299:99–107PubMedCrossRefGoogle Scholar
  2. Anderson G, Lane PJ, Jenkinson EJ (2007) Generating intrathymic microenvironments to establish T-cell tolerance. Nat Rev Immunol 7:954–963PubMedCrossRefGoogle Scholar
  3. Anderson G, Moore NC, Owen JJ, Jenkinson EJ (1996) Cellular interactions in thymocyte development. Annu Rev Immunol 14:73–99PubMedCrossRefGoogle Scholar
  4. Antohe F, Popov D, Radulescu L, Simionescu N, Borchers T, Spener F, Simionescu M (1998) Heart microvessels and aortic endothelial cells express the 15 kDa heart-type fatty acid-binding proteins. Eur J Cell Biol 76:102–109PubMedCrossRefGoogle Scholar
  5. Augustin HG, Braun K, Telemenakis I, Modlich U, Kuhn W (1995) Ovarian angiogenesis. Phenotypic characterization of endothelial cells in a physiological model of blood vessel growth and regression. Am J Pathol 147:339–351PubMedGoogle Scholar
  6. Brix S, Lund P, Kjaer TM, Straarup EM, Hellgren LI, Frokiaer H (2010) CD4(+) T-cell activation is differentially modulated by bacteria-primed dendritic cells, but is generally down-regulated by n-3 polyunsaturated fatty acids. Immunology 129:338–350PubMedCrossRefGoogle Scholar
  7. Cao WM, Murao K, Imachi H, Hiramine C, Abe H, Yu X, Dobashi H, Wong NC, Takahara J, Ishida T (2004) Phosphatidylserine receptor cooperates with high-density lipoprotein receptor in recognition of apoptotic cells by thymic nurse cells. J Mol Endocrinol 32:497–505PubMedCrossRefGoogle Scholar
  8. Chmurzynska A (2006) The multigene family of fatty acid-binding proteins (FABPs): function, structure and polymorphism. J Appl Genet 47:39–48PubMedCrossRefGoogle Scholar
  9. Chouaib S, Welte K, Mertelsmann R, Dupont B (1985) Prostaglandin E2 acts at two distinct pathways of T lymphocyte activation: inhibition of interleukin 2 production and down-regulation of transferrin receptor expression. J Immunol 135:1172–1179PubMedGoogle Scholar
  10. Defresne MP, Nabarra B, van Vliet E, Willemsen R, van Dongen H, van Ewijk W (1994) The ER-TR4 monoclonal antibody recognizes murine thymic epithelial cells (type 1) and inhibits their capacity to interact with immature thymocytes: immuno-electron microscopic and functional studies. Histochemistry 101:355–363PubMedCrossRefGoogle Scholar
  11. El Kassar N, Lucas PJ, Klug DB, Zamisch M, Merchant M, Bare CV, Choudhury B, Sharrow SO, Richie E, Mackall CL, Gress RE (2004) A dose effect of IL-7 on thymocyte development. Blood 104:1419–1427PubMedCrossRefGoogle Scholar
  12. Ezaki T, Matsuno K, Kotani M (1991) Thymic nurse cells (TNC) in spontaneous thymoma BUF/Mna rats as a model to study their roles in T-cell development. Immunology 73:151–158PubMedGoogle Scholar
  13. Gordon JI, Alpers DH, Ockner RK, Strauss AW (1983) The nucleotide sequence of rat liver fatty acid binding protein mRNA. J Biol Chem 258:3356–3363PubMedGoogle Scholar
  14. Gorjao R, Azevedo-Martins AK, Rodrigues HG, Abdulkader F, Arcisio-Miranda M, Procopio J, Curi R (2009) Comparative effects of DHA and EPA on cell function. Pharmacol Ther 122:56–64PubMedCrossRefGoogle Scholar
  15. Guthmann F, Schachtrup C, Tolle A, Wissel H, Binas B, Kondo H, Owada Y, Spener F, Rustow B (2004) Phenotype of palmitic acid transport and of signalling in alveolar type II cells from E/H-FABP double-knockout mice: contribution of caveolin-1 and PPARgamma. Biochim Biophys Acta 1636:196–204PubMedCrossRefGoogle Scholar
  16. Guyden JC, Pezzano M (2003) Thymic nurse cells: a microenvironment for thymocyte development and selection. Int Rev Cytol 223:1–37PubMedCrossRefGoogle Scholar
  17. Hanhoff T, Lucke C, Spener F (2002) Insights into binding of fatty acids by fatty acid binding proteins. Mol Cell Biochem 239:45–54PubMedCrossRefGoogle Scholar
  18. Hare KJ, Jenkinson EJ, Anderson G (2000) An essential role for the IL-7 receptor during intrathymic expansion of the positively selected neonatal T cell repertoire. J Immunol 165:2410–2414PubMedGoogle Scholar
  19. Hart G, Flaishon L, Shachar I (2007) IL-12 and IL-18 down-regulate B cell migration in an Ly49D-dependent manner. Eur J Immunol 37:1996–2007PubMedCrossRefGoogle Scholar
  20. Haunerland NH, Spener F (2004) Fatty acid-binding proteins–insights from genetic manipulations. Prog Lipid Res 43:328–349PubMedCrossRefGoogle Scholar
  21. Hunt CR, Ro JH, Dobson DE, Min HY, Spiegelman BM (1986) Adipocyte P2 gene: developmental expression and homology of 5’-flanking sequences among fat cell-specific genes. Proc Natl Acad Sci USA 83:3786–3790PubMedCrossRefGoogle Scholar
  22. Ito H, Esashi E, Akiyama T, Inoue J, Miyajima A (2006) IL-18 produced by thymic epithelial cells induces development of dendritic cells with CD11b in the fetal thymus. Int Immunol 18:1253–1263PubMedCrossRefGoogle Scholar
  23. Itoh T, Doi H, Chin S, Nishimura T, Kasahara S (1988) Establishment of mouse thymic nurse cell clones from a spontaneous BALB/c thymic tumor. Eur J Immunol 18:821–824PubMedCrossRefGoogle Scholar
  24. Kim K, Lee CK, Sayers TJ, Muegge K, Durum SK (1998) The trophic action of IL-7 on pro-T cells: inhibition of apoptosis of pro-T1, -T2, and -T3 cells correlates with Bcl-2 and Bax levels and is independent of Fas and p53 pathways. J Immunol 160:5735–5741PubMedGoogle Scholar
  25. Kim KJ, Abrams J, Alphonso M, Pearce M, Thorbecke GJ, Palladino MA (1990) Role of endogenously produced interleukin-6 as a second signal in murine thymocyte proliferation induced by multiple cytokines: regulatory effects of transforming growth factor-beta. Cell Immunol 131:261–271PubMedCrossRefGoogle Scholar
  26. Kitanaka N, Owada Y, Abdelwahab SA, Iwasa H, Sakagami H, Watanabe M, Spener F, Kondo H (2003) Specific localization of epidermal-type fatty acid binding protein in dendritic cells of splenic white pulp. Histochem Cell Biol 120:465–473PubMedCrossRefGoogle Scholar
  27. Kitanaka N, Owada Y, Okuyama R, Sakagami H, Nourani MR, Aiba S, Furukawa H, Watanabe M, Ono M, Ohteki T, Kondo H (2006) Epidermal-type fatty acid binding protein as a negative regulator of IL-12 production in dendritic cells. Biochem Biophys Res Commun 345:459–466PubMedCrossRefGoogle Scholar
  28. Kurtz A, Zimmer A, Schnutgen F, Bruning G, Spener F, Muller T (1994) The expression pattern of a novel gene encoding brain-fatty acid binding protein correlates with neuronal and glial cell development. Development 120:2637–2649PubMedGoogle Scholar
  29. Li Y, Pezzano M, Philp D, Reid V, Guyden J (1992) Thymic nurse cells exclusively bind and internalize CD4+ CD8+ thymocytes. Cell Immunol 140:495–506PubMedCrossRefGoogle Scholar
  30. Liu RZ, Li X, Godbout R (2008) A novel fatty acid-binding protein (FABP) gene resulting from tandem gene duplication in mammals: transcription in rat retina and testis. Genomics 92:436–445PubMedCrossRefGoogle Scholar
  31. Makowski L, Hotamisligil GS (2005) The role of fatty acid binding proteins in metabolic syndrome and atherosclerosis. Curr Opin Lipidol 16:543–548PubMedCrossRefGoogle Scholar
  32. Masouye I, Hagens G, Van Kuppevelt TH, Madsen P, Saurat JH, Veerkamp JH, Pepper MS, Siegenthaler G (1997) Endothelial cells of the human microvasculature express epidermal fatty acid-binding protein. Circ Res 81:297–303PubMedCrossRefGoogle Scholar
  33. Massa S, Balciunaite G, Ceredig R, Rolink AG (2006) Critical role for c-kit (CD117) in T cell lineage commitment and early thymocyte development in vitro. Eur J Immunol 36:526–532PubMedCrossRefGoogle Scholar
  34. McCormack JE, Kappler J, Marrack P, Westcott JY (1991) Production of prostaglandin E2 and prostacyclin by thymic nurse cells in culture. J Immunol 146:239–243PubMedGoogle Scholar
  35. Miyazaki M, Kawamoto H, Kato Y, Itoi M, Miyazaki K, Masuda K, Tashiro S, Ishihara H, Igarashi K, Amagai T, Kanno R, Kanno M (2005) Polycomb group gene mel-18 regulates early T progenitor expansion by maintaining the expression of Hes-1, a target of the Notch pathway. J Immunol 174:2507–2516PubMedGoogle Scholar
  36. Moore TA, von Freeden-Jeffry U, Murray R, Zlotnik A (1996) Inhibition of gamma delta T cell development and early thymocyte maturation in IL-7 −/− mice. J Immunol 157:2366–2373PubMedGoogle Scholar
  37. Muller SM, Terszowski G, Blum C, Haller C, Anquez V, Kuschert S, Carmeliet P, Augustin HG, Rodewald HR (2005) Gene targeting of VEGF-A in thymus epithelium disrupts thymus blood vessel architecture. Proc Natl Acad Sci USA 102:10587–10592PubMedCrossRefGoogle Scholar
  38. Murphy EJ, Owada Y, Kitanaka N, Kondo H, Glatz JF (2005) Brain arachidonic acid incorporation is decreased in heart fatty acid binding protein gene-ablated mice. Biochemistry 44:6350–6360PubMedCrossRefGoogle Scholar
  39. Ogawa E, Owada Y, Ikawa S, Adachi Y, Egawa T, Nemoto K, Suzuki K, Hishinuma T, Kawashima H, Kondo H, Muto M, Aiba S, Okuyama R (2011) Epidermal FABP (FABP5) regulates keratinocyte differentiation by 13(S)-HODE-mediated activation of the NF-kappaB signaling pathway. J Invest Dermatol 131:604–612PubMedCrossRefGoogle Scholar
  40. Oida H, Namba T, Sugimoto Y, Ushikubi F, Ohishi H, Ichikawa A, Narumiya S (1995) In situ hybridization studies of prostacyclin receptor mRNA expression in various mouse organs. Br J Pharmacol 116:2828–2837PubMedCrossRefGoogle Scholar
  41. Owada Y, Suzuki R, Iwasa H, Spener F, Kondo H (2002a) Localization of epidermal-type fatty acid binding protein in the thymic epithelial cells of mice. Histochem Cell Biol 117:55–60PubMedCrossRefGoogle Scholar
  42. Owada Y, Takano H, Yamanaka H, Kobayashi H, Sugitani Y, Tomioka Y, Suzuki I, Suzuki R, Terui T, Mizugaki M, Tagami H, Noda T, Kondo H (2002b) Altered water barrier function in epidermal-type fatty acid binding protein-deficient mice. J Invest Dermatol 118:430–435PubMedCrossRefGoogle Scholar
  43. Owada Y, Yoshimoto T, Kondo H (1996) Spatio-temporally differential expression of genes for three members of fatty acid binding proteins in developing and mature rat brains. J Chem Neuroanat 12:113–122PubMedCrossRefGoogle Scholar
  44. Pezzano M, Philp D, Stephenson S, Li Y, Reid V, Maitta R, Guyden JC (1996) Positive selection by thymic nurse cells requires IL-1 beta and is associated with an increased Bcl-2 expression. Cell Immunol 169:174–184PubMedCrossRefGoogle Scholar
  45. Philp D, Pezzano M, Li Y, Omene C, Boto W, Guyden J (1993) The binding, internalization, and release of thymocytes by thymic nurse cells. Cell Immunol 148:301–315PubMedCrossRefGoogle Scholar
  46. Pompos LJ, Fritsche KL (2002) Antigen-driven murine CD4+ T lymphocyte proliferation and interleukin-2 production are diminished by dietary (n-3) polyunsaturated fatty acids. J Nutr 132:3293–3300PubMedGoogle Scholar
  47. Rockett BD, Salameh M, Carraway K, Morrison K, Shaikh SR (2010) n-3 PUFA improves fatty acid composition, prevents palmitate-induced apoptosis, and differentially modifies B cell cytokine secretion in vitro and ex vivo. J Lipid Res 51:1284–1297PubMedCrossRefGoogle Scholar
  48. Sandal S, Tuneva J, Yilmaz B, Carpenter DO (2009) Effects of cholesterol and docosahexaenoic acid on cell viability and (Ca(2+))(i) levels in acutely isolated mouse thymocytes. Cell Biochem Funct 27:155–161PubMedCrossRefGoogle Scholar
  49. Schroeder F, Petrescu AD, Huang H, Atshaves BP, McIntosh AL, Martin GG, Hostetler HA, Vespa A, Landrock D, Landrock KK, Payne HR, Kier AB (2008) Role of fatty acid binding proteins and long chain fatty acids in modulating nuclear receptors and gene transcription. Lipids 43:1–17PubMedCrossRefGoogle Scholar
  50. Siegenthaler G, Hotz R, Chatellard-Gruaz D, Jaconi S, Saurat JH (1993) Characterization and expression of a novel human fatty acid-binding protein: the epidermal type (E-FABP). Biochem Biophys Res Commun 190:482–487PubMedCrossRefGoogle Scholar
  51. Simpson MA, LiCata VJ, Ribarik Coe N, Bernlohr DA (1999) Biochemical and biophysical analysis of the intracellular lipid binding proteins of adipocytes. Mol Cell Biochem 192:33–40PubMedCrossRefGoogle Scholar
  52. van Vliet E, Melis M, van Ewijk W (1984a) Immunohistology of thymic nurse cells. Cell Immunol 87:101–109PubMedCrossRefGoogle Scholar
  53. Van Vliet E, Melis M, Van Ewijk W (1984b) Monoclonal antibodies to stromal cell types of the mouse thymus. Eur J Immunol 14:524–529PubMedCrossRefGoogle Scholar
  54. von Freeden-Jeffry U, Solvason N, Howard M, Murray R (1997) The earliest T lineage-committed cells depend on IL-7 for Bcl-2 expression and normal cell cycle progression. Immunity 7:147–154CrossRefGoogle Scholar
  55. von Freeden-Jeffry U, Vieira P, Lucian LA, McNeil T, Burdach SE, Murray R (1995) Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine. J Exp Med 181:1519–1526CrossRefGoogle Scholar
  56. Wall R, Ross RP, Fitzgerald GF, Stanton C (2010) Fatty acids from fish: the anti-inflammatory potential of long-chain omega-3 fatty acids. Nutr Rev 68:280–289PubMedCrossRefGoogle Scholar
  57. Watanabe M, Ono T, Kondo H (1991) Immunohistochemical studies on the localisation and ontogeny of heart fatty acid binding protein in the rat. J Anat 174:81–95PubMedGoogle Scholar
  58. Wekerle H, Ketelsen UP (1980) Thymic nurse cells-Ia-bearing epithelium involved in T-lymphocyte differentiation? Nature 283:402–404PubMedCrossRefGoogle Scholar
  59. Wekerle H, Ketelsen UP, Ernst M (1980) Thymic nurse cells: lymphoepithelial cell complexes in murine thymuses: morphological and serological characterization. J Exp Med 151:925–944PubMedCrossRefGoogle Scholar
  60. Yamamoto N, Kaneko I, Motohashi K, Sakagami H, Adachi Y, Tokuda N, Sawada T, Furukawa H, Ueyama Y, Fukunaga K, Ono M, Kondo H, Owada Y (2008) Fatty acid-binding protein regulates LPS-induced TNF-alpha production in mast cells. Prostagland Leukot Essent Fatty Acids 79:21–26CrossRefGoogle Scholar
  61. Yu Q, Erman B, Bhandoola A, Sharrow SO, Singer A (2003) In vitro evidence that cytokine receptor signals are required for differentiation of double positive thymocytes into functionally mature CD8+ T cells. J Exp Med 197:475–487PubMedCrossRefGoogle Scholar
  62. Zubkova I, Mostowski H, Zaitseva M (2005) Up-regulation of IL-7, stromal-derived factor-1 alpha, thymus-expressed chemokine, and secondary lymphoid tissue chemokine gene expression in the stromal cells in response to thymocyte depletion: implication for thymus reconstitution. J Immunol 175:2321–2330PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Yasuhiro Adachi
    • 1
  • Sumie Hiramatsu
    • 1
  • Nobuko Tokuda
    • 1
  • Kazem Sharifi
    • 1
  • Majid Ebrahimi
    • 1
  • Ariful Islam
    • 1
  • Yoshiteru Kagawa
    • 1
  • Linda Koshy Vaidyan
    • 1
  • Tomoo Sawada
    • 1
  • Kimikazu Hamano
    • 2
  • Yuji Owada
    • 1
  1. 1.Department of Organ Anatomy, Graduate School of MedicineYamaguchi UniversityUbeJapan
  2. 2.Department of Surgery and Clinical Science, Graduate School of MedicineYamaguchi UniversityUbeJapan

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