title: In vitro effects of binuclear (η (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.
abstract: 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(η(6)-p-cym)}2μ-(N(∩)N)] (N(∩)N = 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(η(6)-p-cym)(nic)] (R1, nic = nicotinate) and [RuCl2(η(6)-p-cym)(inic)] (R2, inic = isonicotinate) as an immunomodulatory agents capable to direct Th cell differentiation. From all investigated complexes, [{RuCl2(η(6)-p-cym)}2μ-{(3-py)COO(CH2CH2O)4CO(3-py)}] (4) was selected for further study because it did not affect splenocyte viability (in concentration up to 50 μM), but significantly reduced secretion of representative Th1 cytokine, IFN-γ induced by T cell mitogen. Besides IFN-γ, 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.
authors.affiliation: Department of Immunology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Bulevar Despota Stefana 142, 11060, Belgrade, Serbia, mommilja@yahoo.com.
authors.forename: Miljana
authors.initials: M
authors.lastname: Momcilovic
authors.forename: Thomas
authors.initials: T
authors.lastname: Eichhorn
authors.forename: Jana
authors.initials: J
authors.lastname: Blazevski
authors.forename: Harry
authors.initials: H
authors.lastname: Schmidt
authors.forename: Goran N
authors.initials: GN
authors.lastname: Kaluđerović
authors.forename: Stanislava
authors.initials: S
authors.lastname: Stosic-Grujicic
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology*; D000081007:Cymenes; D004952:Esters / Q000737:chemistry / Q000494:pharmacology*; D015151:Immunoblotting; D051379:Mice; D008934:Mitogens / Q000494:pharmacology*; D008958:Models, Molecular; D039821:Monoterpenes / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D016133:Polymerase Chain Reaction; D012428:Ruthenium / Q000737:chemistry; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000187:drug effects*
chemical_list: D056831:Coordination Complexes; D000081007:Cymenes; D004952:Esters; D008934:Mitogens; D039821:Monoterpenes; C007210:4-cymene; D011092:Polyethylene Glycols; D012428:Ruthenium
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