In vitro effects of binuclear (eta (6)-p-cymene)ruthenium(II) complex containing bridging bis(nicotinate)-polyethylene glycol ester ligand on differentiation pathways of murine Th lymphocytes activated by T cell mitogen
2015
Authors:
Momčilović, MiljanaEichhorn, Thomas
Blaževski, Jana
Schmidt, Harry
Kaluđerović, Goran N.
Stošić-Grujičić, Stanislava
Document Type:
Article (Published version)
Metadata
Show full item recordAbstract:
T cell differentiation into distinct T helper (Th) subpopulations is
crucial in governing acquired immune responses as well as some
inflammatory and autoimmune disorders. This study investigated potential
of the novel neutral binuclear ruthenium(II) complexes 1-8 with general
formula {[}\{RuCl2(eta(6)-p-cym)\}(2)mu-((NN)-N-a (c))] ((NN)-N-a (c) =
bis(nicotinate)- and bis(iso-nicotinate)-polyethylene glycol esters;
(3-py)COO(CH2CH2O) (n) CO(3-py) and (4-py)COO(CH2CH2O) (n) CO(4-py); n =
1-4), as well as {[}RuCl2(eta(6)-p-cym)(nic)] (R1, nic = nicotinate) and
{[}RuCl2(eta(6)-p-cym)(inic)] (R2, inic = isonicotinate) as an
immunomodulatory agents capable to direct Th cell differentiation. From
all investigated complexes,
{[}\{RuCl2(eta(6)-p-cym)\}(2)mu-\{(3-py)COO(CH2CH2O)(4)CO(3-py)\}] (4)
was selected for further study because it did not affect splenocyte
viability (in concentration up to 50 mu M), but significantly reduced
secretion of representative Th1 cytokine, IFN-gamma induced by T cell
mitogen. Besides IFN-gamma, 4 inhibited dose dependently expression and
production of representative Th17 cytokine, IL-17, in these cells.
Otherwise, the production of anti-inflammatory cytokines IL-4 and IL-10
was upregulated. Also, 4 significantly increased CD4(+)CD25(+)FoxP3(+)
Treg cell frequency in the activated splenocytes. Moreover, ConA-induced
expression of Th1 transcription factors, T-bet and STAT1, as well as of
Th17-related protein STAT3 was attenuated upon exposure to 4, while the
expression of Th2-related transcription factor GATA3 remained stable. In
conclusion, ruthenium(II) complex 4 modulates immune system cell
functions in vitro by inhibiting T cell differentiation towards
pathogenic Th1/Th17 phenotype and inducing a regulatory phenotype
characterized by IL-10 and IL-4 production, which may provide novel
therapeutic opportunities for immune-inflammatory and/or autoimmune
disorders.
Keywords:
Ruthenium(II); T helper cell; Differentiation; Inflammation; CytokineSource:
Journal of Biological Inorganic Chemistry, 2015, 20, 3, 575-583
DOI: 10.1007/s00775-015-1242-x
ISSN: 1432-1327