Skip to main content
SpringerLink
Log in

Vagotomy Affects Lipopolysaccharide-Induced Changes of Urocortin 2 Gene Expression in the Brain and on the Periphery

  • Brief Communication
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

The corticotropin-releasing hormone family of peptides is involved in regulating the neuroendocrine stress response. Also, the vagus nerve plays an important role in the transmission of immune system-related signals to brain structures, thereby orchestrating the neuroendocrine stress response. Therefore, we investigated gene expression of urocortin 2 (Ucn2) and c-fos, a markers of neuronal activity, within the hypothalamic paraventricular nucleus (PVN), a brain structure involved in neuroendocrine and neuroimmune responses, as well as in the adrenal medulla and spleen in vagotomized rats exposed to immune challenge. In addition, markers of neuroendocrine stress response activity were investigated in the adrenal medulla, spleen, and plasma. Intraperitoneal administration of lipopolysaccharide (LPS) induced a significant increase of c-fos and Ucn2 gene expression in the PVN, and adrenal medulla as well as increases of plasma corticosterone levels. In addition, LPS administration induced a significant increase in the gene expression of tyrosine hydroxylase (TH) and phenylethanolamine N-methyltransferase (PNMT) in the adrenal medulla. In the spleen, LPS administration increased gene expression of c-fos, while gene expression of TH and PNMT was significantly reduced, and gene expression of Ucn2 was not affected. Subdiaphragmatic vagotomy significantly attenuated the LPS-induced increases of gene expression of c-fos and Ucn2 in the PVN and Ucn2 in the adrenal medulla. Our data has shown that Ucn2 may be involved in regulation of the HPA axis in response to immune challenge. In addition, our findings indicate that the effect of immune challenge on gene expression of Ucn2 is mediated by vagal pathways.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Availability of Data and Material

All data presented in this manuscript can be accessed by contacting the corresponding author.

References

  1. Deussing JM, Chen A (2018) The Corticotropin-releasing factor family: physiology of the stress response. Physiol Rev 98:2225–2286

    Article  CAS  Google Scholar 

  2. Tillinger A, Horvathova L, Nostramo R, Serova LI, Kvetnansky R, Sabban EL, Mravec B (2018) Glucocorticoid withdrawal affects stress-induced changes of urocortin 2 gene expression in rat adrenal medulla and brain. J Neuroendocrinol 30:e12595

    Article  Google Scholar 

  3. Tillinger A, Nostramo R, Kvetnansky R, Serova L, Sabban EL (2013) Stress-induced changes in gene expression of urocortin 2 and other CRH peptides in rat adrenal medulla: involvement of glucocorticoids. J Neurochem 125:185–192

    Article  CAS  Google Scholar 

  4. Fekete EM, Zorrilla EP (2007) Physiology, pharmacology, and therapeutic relevance of urocortins in mammals: ancient CRF paralogs. Front Neuroendocrinol 28:1–27

    Article  CAS  Google Scholar 

  5. Dermitzaki E, Tsatsanis C, Minas V, Chatzaki E, Charalampopoulos I, Venihaki M, Androulidaki A, Lambropoulou M, Spiess J, Michalodimitrakis E, Gravanis A, Margioris AN (2007) Corticotropin-releasing factor (CRF) and the urocortins differentially regulate catecholamine secretion in human and rat adrenals, in a CRF receptor type-specific manner. Endocrinology 148:1524–1538

    Article  CAS  Google Scholar 

  6. Monteiro-Pinto C, Adao R, Leite-Moreira AF, Bras-Silva C (2019) Cardiovascular effects of Urocortin-2: pathophysiological mechanisms and therapeutic potential. Cardiovasc Drugs Ther 33:599–613

    Article  CAS  Google Scholar 

  7. Janssen D, Kozicz T (2013) Is it really a matter of simple dualism? Corticotropin-releasing factor receptors in body and mental health. Front Endocrinol (Lausanne) 4:28

    Article  Google Scholar 

  8. Zhu H, Wang J, Li J, Li S (2011) Corticotropin-releasing factor family and its receptors: pro-inflammatory or anti-inflammatory targets in the periphery? Inflamm Res 60:715–721

    Article  CAS  Google Scholar 

  9. Goehler LE, Gaykema RP, Hansen MK, Anderson K, Maier SF, Watkins LR (2000) Vagal immune-to-brain communication: a visceral chemosensory pathway. Auton Neurosci 85:49–59

    Article  CAS  Google Scholar 

  10. Wan W, Janz L, Vriend CY, Sorensen CM, Greenberg AH, Nance DM (1993) Differential induction of c-Fos immunoreactivity in hypothalamus and brain stem nuclei following central and peripheral administration of endotoxin. Brain Res Bull 32:581–587

    Article  CAS  Google Scholar 

  11. Nobel CS, Schultzberg M (1995) Induction of interleukin-1 beta mRNA and enkephalin mRNA in the rat adrenal gland by lipopolysaccharides studied by in situ hybridization histochemistry. Neuroimmunomodulation 2:61–73

    Article  CAS  Google Scholar 

  12. Wan W, Wetmore L, Sorensen CM, Greenberg AH, Nance DM (1994) Neural and biochemical mediators of endotoxin and stress-induced c-fos expression in the rat brain. Brain Res Bull 34:7–14

    Article  CAS  Google Scholar 

  13. Coupland RE, Parker TL, Kesse WK, Mohamed AA (1989) The innervation of the adrenal gland. III. Vagal innervation. J Anat 163:173–181

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Bassi GS, Kanashiro A, Coimbra NC, Terrando N, Maixner W, Ulloa L (2020) Anatomical and clinical implications of vagal modulation of the spleen. Neurosci Biobehav Rev 112:363–373

    Article  CAS  Google Scholar 

  15. Ondicova K, Mravec B (2010) Multilevel interactions between the sympathetic and parasympathetic nervous systems: a minireview. Endocr Regul 44:69–75

    Article  CAS  Google Scholar 

  16. Khasar SG, Green PG, Miao FJ, Levine JD (2003) Vagal modulation of nociception is mediated by adrenomedullary epinephrine in the rat. Eur J Neurosci 17:909–915

    Article  Google Scholar 

  17. Ondicova K, Tillinger A, Pecenak J, Mravec B (2019) The vagus nerve role in antidepressants action: efferent vagal pathways participate in peripheral anti-inflammatory effect of fluoxetine. Neurochem Int 125:47–56

    Article  CAS  Google Scholar 

  18. Palkovits M, Brownstein MJ (1988) Maps and guide to microdissection of the rat brain. Elsevier Science Publishing Co., New York

    Google Scholar 

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

    Article  CAS  Google Scholar 

  20. Mravec B, Ondicova K, Tillinger A, Pecenak J (2015) Subdiaphragmatic vagotomy enhances stress-induced epinephrine release in rats. Auton Neurosci 190:20–25

    Article  CAS  Google Scholar 

  21. Elenkov IJ, Kovacs K, Kiss J, Bertok L, Vizi ES (1992) Lipopolysaccharide is able to bypass corticotrophin-releasing factor in affecting plasma ACTH and corticosterone levels: evidence from rats with lesions of the paraventricular nucleus. J Endocrinol 133:231–236

    Article  CAS  Google Scholar 

  22. Gaykema RP, Dijkstra I, Tilders FJ (1995) Subdiaphragmatic vagotomy suppresses endotoxin-induced activation of hypothalamic corticotropin-releasing hormone neurons and ACTH secretion. Endocrinology 136:4717–4720

    Article  CAS  Google Scholar 

  23. Kapcala LP, He JR, Gao Y, Pieper JO, DeTolla LJ (1996) Subdiaphragmatic vagotomy inhibits intra-abdominal interleukin-1 beta stimulation of adrenocorticotropin secretion. Brain Res 728:247–254

    Article  CAS  Google Scholar 

  24. Wang X, Wang BR, Zhang XJ, Duan XL, Guo X, Ju G (2004) Fos expression in the rat brain after intraperitoneal injection of Staphylococcus enterotoxin B and the effect of vagotomy. Neurochem Res 29:1667–1674

    Article  CAS  Google Scholar 

  25. Goehler LE, Gaykema RP, Hammack SE, Maier SF, Watkins LR (1998) Interleukin-1 induces c-Fos immunoreactivity in primary afferent neurons of the vagus nerve. Brain Res 804:306–310

    Article  CAS  Google Scholar 

  26. Maruyama H, Makino S, Noguchi T, Nishioka T, Hashimoto K (2007) Central type 2 corticotropin-releasing hormone receptor mediates hypothalamic-pituitary-adrenocortical axis activation in the rat. Neuroendocrinology 86:1–16

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Author would like to thank Dr. Katarina Ondicova, PhD. for her technical assistance.

Funding

This work was supported by the VEGA grant No. 2/0015/19 and EU grant from cross-border cooperation program Interreg V-A SK-AT V014 – NutriAging.

Author information

Authors and Affiliations

  1. Institute of Experimental Endocrinology, Biomedical Research Center of the Slovak Academy of Sciences, Bratislava, Slovakia

    Andrej Tillinger & Boris Mravec

  2. Institute of Physiology, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia

    Boris Mravec

Authors
  1. Andrej Tillinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Boris Mravec
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

BM designed the experiment; AT, BM performed experiment and analyzed data; AT, BM wrote the manuscript.

Corresponding author

Correspondence to Andrej Tillinger.

Ethics declarations

Conflict of interest

The authors of the manuscript have no conflicts of interest to declare.

Ethics Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. Animal experimental procedures were approved by Animal Health and Animal Welfare Division of the State Veterinary and Food Administration of the Slovak Republic (permission no. Ro 331/16–221) and were in accordance with the Council Directive 2010/63EU of the European Parliament and the Council of 22 September 2010 on the protection of animals used for scientific purposes.

Consent for Publication

We confirm that the manuscript has been read and approved by all named authors. We further confirm that the order of authors listed in the manuscript has been approved by all of us.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tillinger, A., Mravec, B. Vagotomy Affects Lipopolysaccharide-Induced Changes of Urocortin 2 Gene Expression in the Brain and on the Periphery. Neurochem Res 46, 159–164 (2021). https://doi.org/10.1007/s11064-020-03165-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-020-03165-1

Keywords

Search

Navigation