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

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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.

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Abbreviations

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

References

  1. Gregori, S. (2011) Dendritic cells in networks of immuno–logical tolerance, Tissue Antigens, 77, 89–99.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  11. Fantuzzi, G., and Faggioni, R. (2000) Leptin in the regula–tion of immunity, inflammation, and hematopoiesis, J. Leukoc. Biol., 68, 437–446.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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. 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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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. Shirshev, S. V. (2010) AMP–dependent mechanisms of endocrine control of immune system in pregnancy, Usp. Sovrem. Biol., 130, 26–30.

    Google Scholar 

  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.

    Book  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hardie, L., and Trayhurn, P. (1997) Circulating leptin in women: longitudinal study in menstrual cycle and during pregnancy, Clin. Endocrinol., 47, 101–106.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ferguson, G. D., and Daniel, R. S. (2004) Why calcium–stimulated adenylyl cyclases? Physiology, 19, 271–276.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  47. Fruhbeck, G. (2006) Intracellular signalling pathways acti–vated by leptin, Biochem. J., 393, 7–20.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Perm Federal Research Center, Institute of Ecology and Genetics of Microorganisms, Ural Branch of the Russian Academy of Sciences, 614081, Perm, Russia

    E. G. Orlova, S. V. Shirshev & O. A. Loginova

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  1. E. G. Orlova
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  2. S. V. Shirshev
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  3. O. A. Loginova
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Correspondence to E. G. Orlova.

Additional information

Originally published in Biochemistry (Moscow) On-Line Papers in Press, as Manuscript BM18-187, November 12, 2018.

Published in Russian in Biokhimiya, 2019, Vol. 84, No. 1, pp. 63–73.

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Orlova, E.G., Shirshev, S.V. & Loginova, O.A. Mechanisms of Leptin and Ghrelin Action on Maturation and Functions of Dendritic Cells. Biochemistry Moscow 84, 1–10 (2019). https://doi.org/10.1134/S0006297919010012

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  • DOI: https://doi.org/10.1134/S0006297919010012

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