Advertisement

Biochemistry (Moscow)

, Volume 84, Issue 1, pp 1–10 | Cite as

Mechanisms of Leptin and Ghrelin Action on Maturation and Functions of Dendritic Cells

  • E. G. OrlovaEmail author
  • S. V. Shirshev
  • O. A. Loginova
Article
  • 2 Downloads

Abstract

Molecular mechanisms of the immunomodulatory effects of leptin and ghrelin in concentrations typical for preg–nancy on the maturation and functional activity of dendritic cells (DCs) generated from the peripheral blood monocytes of women are investigated. The presence of leptin during DC maturation did not affect the levels of CD83+CD1c+, CD86+CD1c+, and HLA–DR+CD1c+ DCs, but increased the amount and the activity of the enzyme indoleamine 2,3–dioxygenase (IDO). Cell culturing in the presence of ghrelin or combination of leptin and ghrelin reduced the percentage of CD86+CD1c+ DCs but did not affect the levels of CD83+CD1c+ and HLA–DR+CD1c+ DCs. In addition, ghrelin reduced the number of IDO molecules without affecting its activity. Simultaneous presence of leptin and ghrelin increased induced IDO activity without affecting the amount of the enzyme in DCs. The effects of leptin and ghrelin on the investi–gated functions of DCs in some cases correlated with high levels of cAMP. New mechanisms for leptin and ghrelin regula–tion of tolerogenic functions of DCs in pregnancy are proposed.

Keywords

leptin ghrelin pregnancy dendritic cells IDO cAMP 

Abbreviation

AC

adenylate cyclase

AMPK

AMP-activated protein kinase

CaM

calmodulin

cAMP

3′,5′-cyclic adenosine monophosphate

CDs

clusters of differentiation, molecule expressed on the surface of immune system cells

CREB

cAMP response element-binding (CRE)

DAG

diacylglycerol

DC

dendritic cell

Epac

exchange protein directly activated by cAMP

ERK

extracellular signal-regulated kinase

GHS-R

receptor of ghrelin

HLA-DR

human leukocyte antigen DR

IDO

indoleamine 2,3-dioxygenase

IL

interleukin

IP3

inositol 1,4,5-triphosphate

ITIM2

immunoreceptor tyrosine-based inhibito-ry motifs 2

JAK

Janus kinase

JNK

c-Jun N-terminal kinase

LepR

receptor of leptin

LPS

lipopolysaccharide

MAPK

mito-gen-activated protein kinase

MyD88

myeloid differentiation primary response 88

NF-κB

nuclear factor kappa-light-chain-enhancer of activated B cells

p38MAPK

p38 mitogen-activated protein kinase

PDE3B

phosphodiesterase 3B

PI3K

phospho-inositide 3-kinase

PIP2

phosphatidylinositol 4,5-bisphosphate

PKA

protein kinase A

PKB(Akt)

protein kinase B

PKC

pro-tein kinase C

PLC

phospholipase C

SOCS3

suppressors of cytokine signaling 3

STAT3

signal transducer and activator of tran-scription-3

TLR-4

Toll-like receptor-4

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Gregori, S. (2011) Dendritic cells in networks of immuno–logical tolerance, Tissue Antigens, 77, 89–99.CrossRefGoogle Scholar
  2. 2.
    Braun, D., Longman, R. S., and Albert, M. L. (2005) A two–step induction of indoleamine 2,3–dioxygenase (IDO) activ–ity during dendritic cell maturation, Blood, 106, 2375–2381.CrossRefGoogle Scholar
  3. 3.
    Koldehoff, M., and Elmaagacli, A. H. (2013) Thoughts on feto–maternal tolerance: is there a lesson to be learned from allogeneic haematopoietic stem cell transplantation? Cell Biol. Int., 37, 766–767.CrossRefGoogle Scholar
  4. 4.
    Miwa, N., Hayakawa, S., Miyazaki, S., Myojo, S., Sasaki, Y., Sakai, M., Takikawa, O., and Saito, S. (2005) IDO expression on decidual and peripheral blood dendritic cells and mono–cytes/macrophages after treatment with CTLA–4 or interfer–on–gamma increase in normal pregnancy but decrease in spontaneous abortion, Mol. Hum. Reprod., 11, 865–870.CrossRefGoogle Scholar
  5. 5.
    Kamimura, S., Eguchi, K., Yonezawa, M., and Sekiba, K. (1991) Localization and developmental change of indoleamine 2,3–dioxygenase activity in the human placen–ta, Acta. Med. Okayama., 45, 135–139.Google Scholar
  6. 6.
    Fallarino, F., Grohmann, U., Vacca, C., Bianchi, R., Orabona, C., Fioretti, M. C., and Puccetti, P. (2002) T cell apoptosis by tryptophan catabolism, Cell. Death Differ., 9, 1069–1077.CrossRefGoogle Scholar
  7. 7.
    Munn, D. H., Zhou, M., Attwood, J. T., Bondarev, I., Conway, S. J., Marshall, B., Brown, C., and Mellor, A. L. (1998) Prevention of allogeneic fetal rejection by trypto–phan catabolism, Science, 281, 1191–1193.CrossRefGoogle Scholar
  8. 8.
    Baban, B., Chandler, P. R., Sharma, M. D., Pihkala, J., Koni, P. A., Munn, D. H., and Mellor, A. L. (2009) IDO activates regulatory T cells and blocks their conversion into Th17–like T cells, J. Immunol., 183, 2475–2483.CrossRefGoogle Scholar
  9. 9.
    Kudo, Y., Boyd, C. A., Sargent, I. L., and Redman, C. W. (2001) Tryptophan degradation by human placental indoleamine 2,3–dioxygenase regulates lymphocyte prolif–eration, J. Physiol., 535, 207–215.CrossRefGoogle Scholar
  10. 10.
    Tena–Sempere, M. (2013) Interaction between energy homeostasis and reproduction: effects of leptin and ghrelin on the reproductive axis, Horm. Metab. Res., 45, 919–927.CrossRefGoogle Scholar
  11. 11.
    Fantuzzi, G., and Faggioni, R. (2000) Leptin in the regula–tion of immunity, inflammation, and hematopoiesis, J. Leukoc. Biol., 68, 437–446.Google Scholar
  12. 12.
    Dixit, V. D., Schaffer, E. M., Pyle, R. S., Collins, G. D., Sakthivel, S. K., Palaniappan, R., Lillard, J. W., and Taub, D. D. (2004) Ghrelin inhibits leptin–and activation–induced proinflammatory cytokine expression by human T cells, J. Clin. Invest., 1, 57–66.CrossRefGoogle Scholar
  13. 13.
    Shirshev, S. V. (2015) Molecular mechanisms of hormonal and hormonal–cytokine control of immune tolerance in pregnancy, Biochemistry (Moscow). Ser. A. Membr. Cell Biol., 9, 21–40.Google Scholar
  14. 14.
    Orlova, E. G., Shirshev, S. V., and Loginova, O. A. (2015) Leptin and ghrelin regulate dendritic cell maturation and dendritic cell induction of regulatory T–cells, Dokl. Biol. Sci., 462, 171–174.CrossRefGoogle Scholar
  15. 15.
    Orlova, E. G., and Shirshev, S. V. (2017) Role of PKA and PI3K in leptin and ghrelin regulation of adaptive subpopu–lations of regulatory CD4+ T–lymphocyte formation, Biochemistry (Moscow), 82, 1061–1072.CrossRefGoogle Scholar
  16. 16.
    Orlova, E. G., and Shirshev, S. V. (2014) Role of leptin and ghrelin in induction of differentiation of IL–17–producing and T–regulatory cells, Bull. Exp. Biol. Med., 156, 819–822.CrossRefGoogle Scholar
  17. 17.
    Mattioli, B., Straface, E., Quaranta, M. G., Giordani, L., and Viora, M. (2005) Leptin promotes differentiation and survival of human dendritic cells and licenses them for Th1 priming, Immunology, 174, 6820–6828.CrossRefGoogle Scholar
  18. 18.
    Mattioli, B., Giordani, L., Quaranta, M. G., and Viora, M. (2009) Leptin exerts an anti–apoptotic effect on human dendritic cells via the PI3K–Akt signaling pathway, FEBS Lett., 583, 1102–1106.CrossRefGoogle Scholar
  19. 19.
    Faggioni, R., Fantuzzi, G., Fuller, J., Feingold, K. R., and Grunfeld, C. (1998) IL–1–beta mediates leptin induction during inflammation, Am. J. Physiol., 274, 204–208.Google Scholar
  20. 20.
    Komori, T., Doi, A., Furuta, H., Wakao, H., Nakao, N., Nakazato, M., Senba, E., and Morikawa, Y. (2010) Regulation of ghrelin signaling by a leptin–induced gene, negative regulatory element–binding protein, in the neu–rons, J. Biol. Chem., 285, 37884–37894.CrossRefGoogle Scholar
  21. 21.
    Lam, Q. L., Zheng, B. J., Jin, D. Y., and Lu, L. (2007) Leptin induces CD40 expression through the activation of Akt in murine dendritic cells, J. Biol. Chem., 282, 27587–27597.CrossRefGoogle Scholar
  22. 22.
    Orlova, E. G., and Shirshev, S. V. (2011) Regulation of lep–tin and ghrelin of IDO activity of monocytes, Vest. Ural Med. Akad. Nauk, 38, 161–162.Google Scholar
  23. 23.
    Shirshev, S. V. (2010) AMP–dependent mechanisms of endocrine control of immune system in pregnancy, Usp. Sovrem. Biol., 130, 26–30.Google Scholar
  24. 24.
    Amarilyo, G., Iikuni, N., Liu, A., Matarese, G., and La Cava, A. (2014) Leptin enhances availability of apoptotic cell–derived self–antigen in systemic lupus erythematosus, PLoS One, 9, e112826.CrossRefGoogle Scholar
  25. 25.
    Sahu, M., Anamthathmakula, P., and Sahu, A. (2015) Phosphodiesterase–3B–cAMP pathway of leptin signalling in the hypothalamus is impaired during the development of diet–induced obesity in FVB/N mice, J. Neuroendocrinol., 27, 293–302.CrossRefGoogle Scholar
  26. 26.
    Talayev, V. Y., Matveichev, A. V., Lomunova, M. A., Talayeva, M. V., Tsaturov, M. E., Zaichenko, I. Y., and Babaykina, O. N. (2010) The effect of human placenta cytotrophoblast cells on the maturation and T cell stimulat–ing ability of dendritic cells in vitro, Clin. Exp. Immunol., 162, 91–99.CrossRefGoogle Scholar
  27. 27.
    Hardie, L., and Trayhurn, P. (1997) Circulating leptin in women: longitudinal study in menstrual cycle and during pregnancy, Clin. Endocrinol., 47, 101–106.CrossRefGoogle Scholar
  28. 28.
    Fuglsang, J., Skjaerbaek, C., Espelund, U., Frystyk, J., Fisker, S., Flyvbjerg, A., and Ovesen, P. (2005) Ghrelin and its relationship to growth hormones during normal preg–nancy, Clin. Endocrinol., 62, 554–559.CrossRefGoogle Scholar
  29. 29.
    Dzionek, A., Fuchs, A., Schmidt, P., Cremer, S., Zysk, M., Miltenyi, S., Buck, D. W., and Schmitz, J. J. (2000) BDCA–2, BDCA–3, and BDCA–4: three markers for dis–tinct subsets of dendritic cells in human peripheral blood, Immunology, 165, 6037–6046.Google Scholar
  30. 30.
    Jung, I. D., Lee, C. M., Jeong, Y. I., Lee, J. S., Han, J., and Park, Y. M. (2007) Differential regulation of indoleamine 2,3–dioxygenase by lipopolysaccharide and interferon gamma in murine bone marrow derived dendritic cells, FEBS Lett., 581, 1449–1456.CrossRefGoogle Scholar
  31. 31.
    Moraes–Vieira, P. M., Larocca, R. A., Bassi, E. J., Peron, J. P., Andrade–Oliveira, V., Wasinski, F., Araujo, R., Thornley, T., Quintana, F. J., Basso, A. S., Strom, T. B., and Camara, N. O. (2014) Leptin deficiency impairs matu–ration of dendritic cells and enhances induction of regula–tory T and Th17 cells, Eur. J. Immunol., 44, 794–806.CrossRefGoogle Scholar
  32. 32.
    Hwang, S. L., Chung, N. P., Chan, J. K., and Lin, C. L. (2005) Indoleamine 2,3–dioxygenase (IDO) is essential for dendritic cell activation and chemotactic responsiveness to chemokines, Cell Res., 15, 167–175.CrossRefGoogle Scholar
  33. 33.
    Fujigaki, H., Saito, K., Fujigaki, S., Takemura, M., Sudo, K., Ishiguro, H., and Seishima, M. (2006) The signal trans–ducer and activator of transcription 1alpha and interferon regulatory factor 1 are not essential for the induction of indoleamine 2,3–dioxygenase by lipopolysaccharide: involvement of p38 mitogen–activated protein kinase and nuclear factor–kappaB pathways, and synergistic effect of several proinflammatory cytokines, J. Biochem., 139, 655–662.CrossRefGoogle Scholar
  34. 34.
    Borges, B. C., Garcia–Galiano, D., Rorato, R., Elias, L. L., and Elias, C. F. (2016) PI3K p110β subunit in leptin receptor expressing cells is required for the acute hypopha–gia induced by endotoxemia, Mol. Metab., 5, 379–391.CrossRefGoogle Scholar
  35. 35.
    Niswender, K. D., Gallis, B., Blevins, J. E., Corson, M. A., Schwartz, M. W., and Baskin, D. G. (2003) Immunocytochemical detection of phosphatidylinositol 3–kinase activation by insulin and leptin, J. Histochem. Cytochem., 3, 275–283.CrossRefGoogle Scholar
  36. 36.
    Mrak, E., Casati, L., Pagani, F., Rubinacci, A., Zarattini, G., and Sibilia, V. (2015) Ghrelin increases beta–catenin level through protein kinase A activation and regulates OPG expression in rat primary osteoblasts, Int. J. Endocrinol., 2015, 547473.CrossRefGoogle Scholar
  37. 37.
    Kola, B., Hubina, E., Tucci, S. A., Kirkham, T. C., Garcia, E. A., Mitchell, S. E., Williams, L. M., Hawley, S. A., Hardie, D. G., Grossman, A. B., and Korbonits, M. (2005) Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP–activated protein kinase, J. Biol. Chem., 280, 25196–25201.CrossRefGoogle Scholar
  38. 38.
    Schellekens, H., Dinan, T. G., and Cryan, J. F. (2013) Taking two to tango: a role for ghrelin receptor heterodimer–ization in stress and reward, Front. Neurosci., 7, 148.CrossRefGoogle Scholar
  39. 39.
    Fujitsuka, N., Asakawa, A., Morinaga, A., Amitani, M. S., Amitani, H., Katsuura, G., Sawada, Y., Sudo, Y., Uezono, Y., Mochiki, E., Sakata, I., Sakai, T., Hanazaki, K. H., Asaka, M., and Inui, A. (2016) Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuin1, Mol. Psychiatry, 21, 1613–1623.CrossRefGoogle Scholar
  40. 40.
    Yu, J., Wang, Y., Yan, F., Zhang, P., Li, H., Zhao, H., Yan, C., Yan, F., and Ren, X. (2014) Noncanonical NF–κB acti–vation mediates STAT3–stimulated IDO upregulation in myeloid–derived suppressor cells in breast cancer, J. Immunol., 193, 2574–2586.CrossRefGoogle Scholar
  41. 41.
    Heldsinger, A., Grabauskas, G., Wu, X., Zhou, S., Song, I., and Owyang, C. (2014) Ghrelin induces leptin resistance by activation of suppressor of cytokine signaling 3 expression in male rats: implications in satiety regulation, Endocrinology, 155, 3956–3969.CrossRefGoogle Scholar
  42. 42.
    Ferguson, G. D., and Daniel, R. S. (2004) Why calcium–stimulated adenylyl cyclases? Physiology, 19, 271–276.CrossRefGoogle Scholar
  43. 43.
    Bayliss, J. A., Lemus, M. B., Stark, R., Santos, V. V., Thompson, A., Rees, D. J., Galic, S., Elsworth, J. D., Kemp, B. E., Davies, J. S., and Andrews, Z. B. (2016) Ghrelin–AMPK signaling mediates the neuroprotective effects of calorie restriction in Parkinson’s disease, J. Neurosci., 36, 3049–3063.CrossRefGoogle Scholar
  44. 44.
    Orabona, C., Pallotta, M. T., Volpi, C., Fallarino, F., Vacca, C., Bianchi, R., Belladonna, M. L., Fioretti, M. C., Grohmann, U., and Puccetti, P. (2008) SOCS3 drives pro–teasomal degradation of indoleamine 2,3–dioxygenase (IDO) and antagonizes IDO–dependent tolerogenesis, Proc. Natl. Acad. Sci. USA, 105, 20828–20833.CrossRefGoogle Scholar
  45. 45.
    Baravalle, G., Park, H., McSweeney, M., Ohmura–Hoshino, M., Matsuki, Y., Ishido, S., and Shin, J. S. (2011) Ubiquitination of CD86 is a key mechanism in regulating antigen presentation by dendritic cells, J. Immunol., 187, 2966–2973.CrossRefGoogle Scholar
  46. 46.
    Ardeshna, K. M., Pizzey, A. R., Devereux, S., and Khwaja, A. (2000) The PI3 kinase, p38SAP kinase, and NF–kappa B signal transduction pathways are involved in the survival and maturation of lipopolysaccharide–stimu–lated human monocyte–derived dendritic cells, Blood, 96, 1039–1046.Google Scholar
  47. 47.
    Fruhbeck, G. (2006) Intracellular signalling pathways acti–vated by leptin, Biochem. J., 393, 7–20.CrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Inc. 2019

Authors and Affiliations

  • E. G. Orlova
    • 1
    Email author
  • S. V. Shirshev
    • 1
  • O. A. Loginova
    • 1
  1. 1.Perm Federal Research Center, Institute of Ecology and Genetics of MicroorganismsUral Branch of the Russian Academy of SciencesPermRussia

Personalised recommendations