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Role of PKA and PI3K in leptin and ghrelin regulation of adaptive subpopulations of regulatory CD4+ T-lymphocyte formation

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Abstract

The role of phosphatidylinositol-3 kinase (PI3K) and protein kinase A (PKA) in leptin and ghrelin regulation of formation of adaptive (a) subpopulations of CD4+ T-lymphocytes (helper (h) cells producing interleukin-17A) (aTh17) and of T-regulatory lymphocytes (aTreg) in the context of physiological pregnancy is established. It is shown that leptin at a concentration typical for the second half of pregnancy (trimesters II-III) enhances the differentiation of aTh17 with a high level of interleukin-17A (IL-17A) production and the expression of the chemokine receptor CCR6 with the participation of PI3K. Simultaneously, leptin reduces formation of aTreg expressing the suppressor molecule CTLA-4, which determines the function of these cells. Ghrelin at a concentration characteristic of the first half of pregnancy (trimesters I-II), in contrast, enhances aTreg formation and, in parallel, reduces the level aTh17 (that express CCR6) and the IL-17A production by aTh17. PKA, likewise PI3K, participates in regulatory effects of ghrelin on the formation of aTh17 and aTreg. The combined action of leptin and ghrelin (via PKA participation) enhances formation of only aTreg, which determines the priority of this molecular mechanism and explains why the investigated hormones with reciprocal differentiating potential do not come into antagonism at the level of immune system cells during pregnancy.

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Abbreviations

Ac:

adenylate cyclase

Akt (PKB):

protein kinase B

AMPK:

AMP-activated protein kinase

cAMP:

3′,5′-cyclic adenosine monophosphate

CCR6:

chemokine receptor

CD:

membrane molecule of cells of the immune system

CREB:

cAMP response element (CRE)-binding (protein)

CTLA-4:

cytotoxic T-lymphocyte-associated antigen-4

FoxO1/3a:

proteins of FoxOfamily

FOXP3:

transcription factor of Treg differentiation

GHS-R:

growth hormone secretagogue receptor (ghrelin receptor)

IFN:

interferon

IL:

interleukin

IP3 :

inositol-1,4,5-trisphosphate

IRS-2:

insulin receptor substrate 2

Jak:

Janus kinase

LepR:

leptin receptor

mTORC1(2):

mammalian target of rapamycin complex 1(2)

PDE:

phosphodiesterase

PI3K:

phosphatidylinositol-3-kinase

PKA:

protein kinase A

PKC:

protein kinase C

PLC:

phospholipase C

RORC:

transcription factor of Th17 differentiation

S6K1-S6:

ribosomal protein kinase 1

STAT3:

signal transducer and activator of transcription 3

TGF-β1:

transforming growth factor β1

Th17:

IL-17-producing lymphocytes

Treg:

T-regulatory lymphocytes

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

    E. G. Orlova & S. V. Shirshev

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  1. E. G. Orlova
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Correspondence to E. G. Orlova.

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Published in Russian in Biokhimiya, 2017, Vol. 82, No. 9, pp. 1361-1373.

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Orlova, E.G., Shirshev, S.V. Role of PKA and PI3K in leptin and ghrelin regulation of adaptive subpopulations of regulatory CD4+ T-lymphocyte formation. Biochemistry Moscow 82, 1061–1072 (2017). https://doi.org/10.1134/S0006297917090103

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  • DOI: https://doi.org/10.1134/S0006297917090103

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