Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Bone marrow cells produce a novel TSHβ splice variant that is upregulated in the thyroid following systemic virus infection

Genes & Immunity volume 10, pages 18–26 (2009)Cite this article

Abstract

Although cells of the immune system can produce thyroid-stimulating hormone (TSH), the significance of that remains unclear. Using 5′ rapid amplification of cDNA ends (RACE), we show that mouse bone marrow (BM) cells produce a novel in-frame TSHβ splice variant generated from a portion of intron 4 with all of the coding region of exon 5, but none of exon 4. The TSHβ splice variant gene was expressed at low levels in the pituitary, but at high levels in the BM and the thyroid, and the protein was secreted from transfected Chinese hamster ovary (CHO) cells. Immunoprecipitation identified an 8 kDa product in lysates of CHO cells transfected with the novel TSHβ construct, and a 17 kDa product in lysates of CHO cells transfected with the native TSHβ construct. The splice variant TSHβ protein elicited a cAMP response from FRTL-5 thyroid follicular cells and a mouse alveolar macrophage (AM) cell line. Expression of the TSHβ splice variant, but not the native form of TSHβ, was significantly upregulated in the thyroid during systemic virus infection. These studies characterize the first functional splice variant of TSHβ, which may contribute to the metabolic regulation during immunological stress, and may offer a new perspective for understanding autoimmune thyroiditis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Kelly GS . Peripheral metabolism of thyroid hormones: a review. Altern Med Rev 2000; 5: 306–333.

    CAS  PubMed  Google Scholar 

  2. Szkudlinski MW, Fremont V, Ronin C, Weintraub BD . Thyroid-stimulating hormone and thyroid-stimulating hormone receptor structure-function relationships. Physiol Rev 2002; 82: 473–502.

    Article  CAS  Google Scholar 

  3. Gordon DF, Wood WM, Ridgway EC . Organization and nucleotide sequence of the gene encoding the beta-subunit of murine thyrotropin. DNA 1988; 7: 17–26.

    Article  CAS  Google Scholar 

  4. Wood WM, Gordon DF, Ridgway EC . Expression of the beta-subunit gene of murine thyrotropin results in multiple messenger ribonucleic acid species which are generated by alternative exon splicing. Mol Endocrinol 1987; 1: 875–883.

    Article  CAS  Google Scholar 

  5. Wolf O, Kourides IA, Gurr JA . Expression of the gene for the beta subunit of mouse thyrotropin results in multiple mRNAs differing in their 5′-untranslated regions. J Biol Chem 1987; 262: 16596–16603.

    CAS  PubMed  Google Scholar 

  6. Shupnik MA . Thyroid hormone suppression of pituitary hormone gene expression. Rev Endocr Metab Disord 2000; 1: 35–42.

    Article  CAS  Google Scholar 

  7. Kruger TE, Smith LR, Harbour DV, Blalock JE . Thyrotropin: an endogenous regulator of the in vitro immune response. J Immunol 1989; 142: 744–747.

    CAS  PubMed  Google Scholar 

  8. Smith EM, Phan M, Kruger TE, Coppenhaver DH, Blalock JE . Human lymphocyte production of immunoreactive thyrotropin. Proc Natl Acad Sci USA 1983; 80: 6010–6013.

    Article  CAS  Google Scholar 

  9. Harbour DV, Kruger TE, Coppenhaver D, Smith EM, Meyer III WJ . Differential expression and regulation of thyrotropin (TSH) in T cell lines. Mol Cell Endocrinol 1989; 64: 229–241.

    Article  CAS  Google Scholar 

  10. Kelley KW, Weigent DA, Kooijman R . Protein hormones and immunity. Brain Behav Immun 2007; 21: 384–392.

    Article  CAS  Google Scholar 

  11. Fabris N, Mocchegiani E, Provinciali M . Pituitary-thyroid axis and immune system: a reciprocal neuroendocrine-immune interaction. Horm Res 1995; 43: 29–38.

    Article  CAS  Google Scholar 

  12. Whetsell M, Bagriacik EU, Seetharamaiah GS, Prabhakar BS, Klein JR . Neuroendocrine-induced synthesis of bone marrow-derived cytokines with inflammatory immunomodulating properties. Cell Immunol 1999; 192: 159–166.

    Article  CAS  Google Scholar 

  13. Dardenne M, Savino W . Interdependence of the endocrine and immune systems. Adv Neuroimmunol 1996; 6: 297–307.

    Article  CAS  Google Scholar 

  14. Bagriacik EU, Zhou Q, Wang HC, Klein JR . Rapid and transient reduction in circulating thyroid hormones following systemic antigen priming: implications for functional collaboration between dendritic cells and thyroid. Cell Immunol 2001; 212: 92–100.

    Article  CAS  Google Scholar 

  15. Wang HC, Dragoo J, Zhou Q, Klein JR . An intrinsic thyrotropin-mediated pathway of TNF-alpha production by bone marrow cells. Blood 2003; 101: 119–123.

    Article  Google Scholar 

  16. Klein JR, Wang HC . Characterization of a novel set of resident intrathyroidal bone marrow-derived hematopoietic cells: potential for immune-endocrine interactions in thyroid homeostasis. J Exp Biol 2004; 207 (Pt 1): 55–65.

    Article  CAS  Google Scholar 

  17. Zhou Q, Wang HC, Klein JR . Characterization of novel anti-mouse thyrotropin monoclonal antibodies. Hybrid Hybridomics 2002; 21: 75–79.

    Article  CAS  Google Scholar 

  18. Patibandla SA, Dallas JS, Seetharamaiah GS, Tahara K, Kohn LD, Prabhakar BS . Flow cytometric analyses of antibody binding to Chinese hamster ovary cells expressing human thyrotropin receptor. J Clin Endocrinol Metab 1997; 82: 1885–1893.

    CAS  PubMed  Google Scholar 

  19. Chico Galdo V, Massart C, Jin L, Vanvooren V, Caillet-Fauquet P, Andry G et al. Acrylamide, an in vivo thyroid carcinogenic agent, induces DNA damage in rat thyroid cell lines and primary cultures. Mol Cell Endocrinol 2006; 257–258: 6–14.

    Article  Google Scholar 

  20. Neufeld DS, Platzer M, Davies TF . Reovirus induction of MHC class II antigen in rat thyroid cells. Endocrinology 1989; 124: 543–545.

    Article  CAS  Google Scholar 

  21. Srinivasappa J, Garzelli C, Onodera T, Ray U, Notkins AL . Virus-induced thyroiditis. Endocrinology 1988; 122: 563–566.

    Article  CAS  Google Scholar 

  22. Ding WQ, Kuntz SM, Miller LJ . A misspliced form of the cholecystokinin-B/gastrin receptor in pancreatic carcinoma: role of reduced sellular U2AF35 and a suboptimal 3′-splicing site leading to retention of the fourth intron. Cancer Res 2002; 62: 947–952.

    CAS  PubMed  Google Scholar 

  23. Chand HS, Ness SA, Kisiel W . Identification of a novel human tissue factor splice variant that is upregulated in tumor cells. Int J Cancer 2006; 118: 1713–1720.

    Article  CAS  Google Scholar 

  24. Sironen A, Thomsen B, Andersson M, Ahola V, Vilkki J . An intronic insertion in KPL2 results in aberrant splicing and causes the immotile short-tail sperm defect in the pig. Proc Natl Acad Sci USA 2006; 103: 5006–5011.

    Article  CAS  Google Scholar 

  25. Jaillon O, Bouhouche K, Gout JF, Aury JM, Noel B, Saudemont B et al. Translational control of intron splicing in eukaryotes. Nature 2008; 451: 359–362.

    Article  CAS  Google Scholar 

  26. Baralle D, Baralle M . Splicing in action: assessing disease causing sequence changes. J Med Genet 2005; 42: 737–748.

    Article  CAS  Google Scholar 

  27. Brown PJ, Kagaya R, Banham AH . Characterization of human FOXP1 isoform 2, using monoclonal antibody 4E3-G11, and intron retention as a tissue-specific mechanism generating a novel FOXP1 isoform. Histopathology 2008; 52: 632–637.

    Article  CAS  Google Scholar 

  28. Galante PA, Sakabe NJ, Kirschbaum-Slager N, de Souza SJ . Detection and evaluation of intron retention events in the human transcriptome. RNA 2004; 10: 757–765.

    Article  CAS  Google Scholar 

  29. Kan Z, States D, Gish W . Selecting for functional alternative splices in ESTs. Genome Res 2002; 12: 1837–1845.

    Article  CAS  Google Scholar 

  30. Black DL . Mechanisms of alternative pre-messenger RNA splicing. Annu Rev Biochem 2003; 72: 291–336.

    Article  CAS  Google Scholar 

  31. Livak KJ, Schmittgen TD . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25: 402–408.

    Article  CAS  Google Scholar 

  32. Montufar-Solis D, Garza T, Teng BB, Klein JR . Upregulation of ICOS on CD43+ CD4+ murine small intestinal intraepithelial lymphocytes during acute reovirus infection. Biochem Biophys Res Commun 2006; 342: 782–790.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by NIH Grants DK035566 and DE015355.

Author information

Authors and Affiliations

  1. Department of Diagnostic Sciences, Dental Branch, The University of Texas Health Science Center, Houston, TX, USA

    B H Vincent, D Montufar-Solis, J Schaefer & J R Klein

  2. Center for Human Genetics, The Brown Foundation of Molecular Medicine for the Prevention of Human Disease, The University of Texas Health Science Center, Houston, TX, USA

    B-B Teng

  3. Department of Environmental and Genetic Medicine, Texas A&M Health Science Center, Houston, TX, USA

    B A Amendt

Authors
  1. B H Vincent
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D Montufar-Solis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B-B Teng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B A Amendt
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Schaefer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J R Klein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J R Klein.

Additional information

Supplementary Information accompanies the paper on Genes and Immunity website (http://www.nature.com/gene)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vincent, B., Montufar-Solis, D., Teng, BB. et al. Bone marrow cells produce a novel TSHβ splice variant that is upregulated in the thyroid following systemic virus infection. Genes Immun 10, 18–26 (2009). https://doi.org/10.1038/gene.2008.69

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gene.2008.69

Keywords

This article is cited by

Search

Advanced search

Quick links