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Signaling of Cytokines is Important in Regulation of GnRH Neurons

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Abstract

Cytokines encompass a broad class of peptides that mediate signals in a broad range of physiological situations including inflammation, infection, and obesity. The cytokine receptor-associated tyrosine kinase, Jak2, is one of the most important proteins mediating cytokine signaling pathway activation. Recently, our group has demonstrated that Jak2 signaling in the gonadotropin-releasing hormone (GnRH) neuron plays a critical role in fertility in males and females, implicating cytokine activation of the neuron in GnRH neuronal development and function. To date, the specific cytokine(s) essential for activating Jak2 during neuroendocrine development are not known. In this article, we review the evidence for the role of several class 1 cytokines in regulating GnRH neuronal development, GnRH secretion, and GnRH expression.

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References

  1. Tomaszewska-Zaremba D, Herman A (2009) The role of immunological system in the regulation of gonadoliberin and gonadotropin secretion. Reprod Biol 9:11–23

    PubMed  Google Scholar 

  2. Arai KI, Lee F, Miyajima A, Miyatake S, Arai N, Yokota T (1990) Cytokines: coordinators of immune and inflammatory responses. Annu Rev Biochem 59:783–836

    Article  PubMed  CAS  Google Scholar 

  3. Rivest S, Rivier C (1993) Central mechanisms and sites of action involved in the inhibitory effects of CRF and cytokines on LHRH neuronal activity. Ann N Y Acad Sci 697:117–141

    Article  PubMed  CAS  Google Scholar 

  4. Rivier C, Vale W (1990) Cytokines act within the brain to inhibit luteinizing hormone secretion and ovulation in the rat. Endocrinology 127:849–856

    Article  PubMed  CAS  Google Scholar 

  5. Porkka-Heiskanen T, Urban JH, Turek FW, Levine JE (1994) Gene expression in a subpopulation of luteinizing hormone–releasing hormone (LHRH) neurons prior to the preovulatory gonadotropin surge. J Neurosci 14(9):5548–5558

    PubMed  CAS  Google Scholar 

  6. Nagatani S, Bucholtz DC, Murahashi K, Estacio MA, Tsukamura H, Foster DL, Maeda KI (1996) Reduction of glucose availability suppresses pulsatile luteinizing hormone release in female and male rats. Endocrinology 137:1166–1170

    Article  PubMed  CAS  Google Scholar 

  7. Bucholtz DC, Chiesa A, Pappano WN, Nagatani S, Tsukamura H, Maeda KI, Foster DL (2000) Regulation of pulsatile luteinizing hormone secretion by insulin in the diabetic male lamb. Biol Reprod 62:1248–1255

    Article  PubMed  CAS  Google Scholar 

  8. Smith MS, Grove KL (2002) Integration of the regulation of reproductive function and energy balance: lactation as a model. Front Neuroendocrinol 23:225–256

    Article  PubMed  CAS  Google Scholar 

  9. Pitteloud N, Quinton R, Pearce S, Raivio T, Acierno J, Dwyer A, Plummer L, Hughes V, Seminara S, Cheng YZ, Li WP, Maccoll G, Eliseenkova AV, Olsen SK, Ibrahimi OA, Hayes FJ, Boepple P, Hall JE, Bouloux P, Mohammadi M, Crowley W (2007) Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism. J Clin Invest 117:457–463

    Article  PubMed  CAS  Google Scholar 

  10. Ihle JN (1995) Cytokine receptor signalling. Nature 377:591–594

    Article  PubMed  CAS  Google Scholar 

  11. Parganas E, Wang D, Stravopodis D, Topham DJ, Marine JC, Teglund S, Vanin EF, Bodner S, Colamonici OR, van Deursen JM, Grosveld G, Ihle JN (1998) Jak2 is essential for signaling through a variety of cytokine receptors. Cell 93:385–395

    Article  PubMed  CAS  Google Scholar 

  12. Pellegrini S, Dusanter-Fourt I (1997) The structure, regulation and function of the Janus kinases (JAKs) and the signal transducers and activators of transcription (STATs). Eur J Biochem 248:615–633

    Article  PubMed  CAS  Google Scholar 

  13. Wu S, Divall S, Hoffman GE, Le WW, Wagner KU, Wolfe A (2011) Jak2 is necessary for neuroendocrine control of female reproduction. J Neurosci 31:184–192

    Article  PubMed  CAS  Google Scholar 

  14. Divall SA, Williams TR, Carver SE, Koch L, Bruning JC, Kahn CR, Wondisford F, Radovick S, Wolfe A (2010) Divergent roles of growth factors in the GnRH regulation of puberty in mice. J Clin Invest 120:2900–2909

    Article  PubMed  CAS  Google Scholar 

  15. Wang YM, Bayliss DA, Millhorn DE, Petrusz P, Joseph DR (1990) The androgen-binding protein gene is expressed in male and female rat brain. Endocrinology 127:3124–3130

    Article  PubMed  CAS  Google Scholar 

  16. Dinarello CA (1996) Biologic basis for interleukin-1 in disease. Blood 87:2095–2147

    PubMed  CAS  Google Scholar 

  17. Allan SM, Tyrrell PJ, Rothwell NJ (2005) Interleukin-1 and neuronal injury. Nat Rev Immunol 5:629–640

    Article  PubMed  CAS  Google Scholar 

  18. Lim H, Kim HP (2011) Matrix metalloproteinase-13 expression in IL-1beta-treated chondrocytes by activation of the p38 MAPK/c-Fos/AP-1 and JAK/STAT pathways. Arch Pharm Res 34:109–117

    Article  PubMed  CAS  Google Scholar 

  19. Breder CD, Dinarello CA, Saper CB (1988) Interleukin-1 immunoreactive innervation of the human hypothalamus. Science 240:321–324

    Article  PubMed  CAS  Google Scholar 

  20. Lechan RM, Toni R, Clark BD, Cannon JG, Shaw AR, Dinarello CA, Reichlin S (1990) Immunoreactive interleukin-1 beta localization in the rat forebrain. Brain Res 514:135–140

    Article  PubMed  CAS  Google Scholar 

  21. Kalra PS, Edwards TG, Xu B, Jain M, Kalra SP (1998) The anti-gonadotropic effects of cytokines: the role of neuropeptides. Domest Anim Endocrinol 15:321–332

    Article  PubMed  CAS  Google Scholar 

  22. Kalra PS, Sahu A, Kalra SP (1990) Interleukin-1 inhibits the ovarian steroid-induced luteinizing hormone surge and release of hypothalamic luteinizing hormone-releasing hormone in rats. Endocrinology 126:2145–2152

    Article  PubMed  CAS  Google Scholar 

  23. Watanobe H, Hayakawa Y (2003) Hypothalamic interleukin-1 beta and tumor necrosis factor-alpha, but not interleukin-6, mediate the endotoxin-induced suppression of the reproductive axis in rats. Endocrinology 144:4868–4875

    Article  PubMed  CAS  Google Scholar 

  24. Dondi D, Limonta P, Montagnani MM, Piva F (1998) Mechanism of action of interleukin-1 in modulating gonadotropin secretion. In vivo and in vitro studies. Biol Signals Recept 7:55–60

    Article  PubMed  CAS  Google Scholar 

  25. Yamaguchi M, Yoshimoto Y, Komura H, Koike K, Matsuzaki N, Hirota K, Miyake A, Tanizawa O (1990) Interleukin 1 beta and tumour necrosis factor alpha stimulate the release of gonadotropin-releasing hormone and interleukin 6 by primary cultured rat hypothalamic cells. Acta Endocrinol (Copenh) 123:476–480

    CAS  Google Scholar 

  26. Rivest S, Torres G, Rivier C (1992) Differential effects of central and peripheral injection of interleukin-1 beta on brain c-fos expression and neuroendocrine functions. Brain Res 587:13–23

    Article  PubMed  CAS  Google Scholar 

  27. Kang SS, Kim SR, Leonhardt S, Jarry H, Wuttke W, Kim K (2000) Effect of interleukin-1beta on gonadotropin-releasing hormone (GnRH) and GnRH receptor gene expression in castrated male rats. J Neuroendocrinol 12:421–429

    Article  PubMed  CAS  Google Scholar 

  28. Gore AC, Yeo TT, Ho A, Roberts JL (1997) Post-transcriptional regulation of the gonadotropin-releasing hormone gene in GT1-7 cells. J Neuroendocrinol 9:271–277

    Article  PubMed  CAS  Google Scholar 

  29. Igaz P, Salvi R, Rey JP, Glauser M, Pralong FP, Gaillard RC (2006) Effects of cytokines on gonadotropin-releasing hormone (GnRH) gene expression in primary hypothalamic neurons and in GnRH neurons immortalized conditionally. Endocrinology 147:1037–1043

    Article  PubMed  CAS  Google Scholar 

  30. Gadient RA, Otten U (1993) Differential expression of interleukin-6 (IL-6) and interleukin-6 receptor (IL-6R) mRNAs in rat hypothalamus. Neurosci Lett 153:13–16

    Article  PubMed  CAS  Google Scholar 

  31. Dozio E, Ruscica M, Galliera E, Corsi MM, Magni P (2009) Leptin, ciliary neurotrophic factor, leukemia inhibitory factor and interleukin-6: class-I cytokines involved in the neuroendocrine regulation of the reproductive function. Curr Protein Pept Sci 10:577–584

    Article  PubMed  CAS  Google Scholar 

  32. Heinrich PC, Behrmann I, Muller-Newen G, Schaper F, Graeve L (1998) Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 334(Pt 2):297–314

    PubMed  CAS  Google Scholar 

  33. Lyson K, McCann SM (1991) The effect of interleukin-6 on pituitary hormone release in vivo and in vitro. Neuroendocrinology 54:262–266

    Article  PubMed  CAS  Google Scholar 

  34. Russell SH, Small CJ, Stanley SA, Franks S, Ghatei MA, Bloom SR (2001) The in vitro role of tumour necrosis factor-alpha and interleukin-6 in the hypothalamic–pituitary gonadal axis. J Neuroendocrinol 13:296–301

    Article  PubMed  CAS  Google Scholar 

  35. Yamaguchi M, Koike K, Yoshimoto Y, Matsuzaki N, Miyake A, Tanizawa O (1991) Interleukin-6 stimulates gonadotropin-releasing hormone secretion from rat hypothalamic cells. Horm Res 35:252–256

    Article  PubMed  CAS  Google Scholar 

  36. Perez C, Albert I, DeFay K, Zachariades N, Gooding L, Kriegler M (1990) A nonsecretable cell surface mutant of tumor necrosis factor (TNF) kills by cell-to-cell contact. Cell 63:251–258

    Article  PubMed  CAS  Google Scholar 

  37. Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259:87–91

    Article  PubMed  CAS  Google Scholar 

  38. Aggarwal BB (2003) Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 3:745–756

    Article  PubMed  CAS  Google Scholar 

  39. Pincheira R, Castro AF, Ozes ON, Idumalla PS, Donner DB (2008) Type 1 TNF receptor forms a complex with and uses Jak2 and c-Src to selectively engage signaling pathways that regulate transcription factor activity. J Immunol 181:1288–1298

    PubMed  CAS  Google Scholar 

  40. Nadeau S, Rivest S (1999) Effects of circulating tumor necrosis factor on the neuronal activity and expression of the genes encoding the tumor necrosis factor receptors (p55 and p75) in the rat brain: a view from the blood–brain barrier. Neuroscience 93:1449–1464

    Article  PubMed  CAS  Google Scholar 

  41. Yoo MJ, Nishihara M, Takahashi M (1997) Tumor necrosis factor-alpha mediates endotoxin induced suppression of gonadotropin-releasing hormone pulse generator activity in the rat. Endocr J 44:141–148

    Article  PubMed  CAS  Google Scholar 

  42. Patterson PH, Fann MJ (1992) Further studies of the distribution of CDF/LIF mRNA. CIBA Found Symp 167:125–135, discussion 135–40

    PubMed  CAS  Google Scholar 

  43. Gearing DP, VandenBos T, Beckmann MP, Thut CJ, Comeau MR, Mosley B, Ziegler SF (1992) Reconstitution of high affinity leukaemia inhibitory factor (LIF) receptors in haemopoietic cells transfected with the cloned human LIF receptor. CIBA Found Symp 167:245–255, discussion 255-9

    PubMed  CAS  Google Scholar 

  44. Boulton TG, Stahl N, Yancopoulos GD (1994) Ciliary neurotrophic factor/leukemia inhibitory factor/interleukin 6/oncostatin M family of cytokines induces tyrosine phosphorylation of a common set of proteins overlapping those induced by other cytokines and growth factors. J Biol Chem 269:11648–11655

    PubMed  CAS  Google Scholar 

  45. Magni P, Dozio E, Ruscica M, Watanobe H, Cariboni A, Zaninetti R, Motta M, Maggi R (2007) Leukemia inhibitory factor induces the chemomigration of immortalized gonadotropin-releasing hormone neurons through the independent activation of the Janus kinase/signal transducer and activator of transcription 3, mitogen-activated protein kinase/extracellularly regulated kinase 1/2, and phosphatidylinositol 3-kinase/Akt signaling pathways. Mol Endocrinol 21:1163–1174

    Article  PubMed  CAS  Google Scholar 

  46. Dobrea GM, Unnerstall JR, Rao MS (1992) The expression of CNTF message and immunoreactivity in the central and peripheral nervous system of the rat. Brain Res Dev Brain Res 66:209–219

    Article  PubMed  CAS  Google Scholar 

  47. Henderson JT, Seniuk NA, Roder JC (1994) Localization of CNTF immunoreactivity to neurons and astroglia in the CNS. Brain Res Mol Brain Res 22:151–165

    Article  PubMed  CAS  Google Scholar 

  48. DeChiara TM, Vejsada R, Poueymirou WT, Acheson A, Suri C, Conover JC, Friedman B, McClain J, Pan L, Stahl N, Ip NY, Yancopoulos GD (1995) Mice lacking the CNTF receptor, unlike mice lacking CNTF, exhibit profound motor neuron deficits at birth. Cell 83:313–322

    Article  PubMed  CAS  Google Scholar 

  49. De Serio A, Graziani R, Laufer R, Ciliberto G, Paonessa G (1995) In vitro binding of ciliary neurotrophic factor to its receptors: evidence for the formation of an IL-6-type hexameric complex. J Mol Biol 254:795–800

    Article  PubMed  Google Scholar 

  50. Davis S, Aldrich TH, Valenzuela DM, Wong VV, Furth ME, Squinto SP, Yancopoulos GD (1991) The receptor for ciliary neurotrophic factor. Science 253:59–63

    Article  PubMed  CAS  Google Scholar 

  51. Masu Y, Wolf E, Holtmann B, Sendtner M, Brem G, Thoenen H (1993) Disruption of the CNTF gene results in motor neuron degeneration. Nature 365:27–32

    Article  PubMed  CAS  Google Scholar 

  52. Stanley SA, Todd JF, Small CJ, Kim MS, Heath MM, Anand P, Ghatei MA, Bloom SR (2000) The effects of ciliary neurotrophic factor on the hypothalamo–pituitary gonadal axis in vitro in female rats. J Neuroendocrinol 12:1009–1013

    Article  PubMed  CAS  Google Scholar 

  53. Watanobe H, Habu S (2001) Ciliary neurotrophic factor, a gp130 cytokine, regulates preovulatory surges of luteinizing hormone and prolactin in the rat. Neuroendocrinology 74:281–287

    Article  PubMed  CAS  Google Scholar 

  54. Dozio E, Watanobe H, Ruscica M, Maggi R, Motta M, Magni P (2005) Expression of functional ciliary neurotrophic factor receptors in immortalized gonadotrophin-releasing hormone-secreting neurones. J Neuroendocrinol 17:286–291

    Article  PubMed  CAS  Google Scholar 

  55. Kisseleva T, Bhattacharya S, Braunstein J, Schindler CW (2002) Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene 285:1–24

    Article  PubMed  CAS  Google Scholar 

  56. Korenbrot CC, Huhtaniemi IT, Weiner RI (1977) Preputial separation as an external sign of pubertal development in the male rat. Biol Reprod 17:298–303

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors gratefully acknowledge the manuscript review by Dr. Sara Divall (Johns Hopkins University).

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  1. Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA

    Sheng Wu & Andrew Wolfe

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  1. Sheng Wu
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  2. Andrew Wolfe
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Correspondence to Sheng Wu.

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Wu, S., Wolfe, A. Signaling of Cytokines is Important in Regulation of GnRH Neurons. Mol Neurobiol 45, 119–125 (2012). https://doi.org/10.1007/s12035-011-8224-y

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