Modulation of human monocyte-derived dendritic cells maturation by a soluble guanylate cyclase activator, YC-1, in a cyclic nucleotide independent manner.
This study evaluated how YC-1, a guanylate cyclase activator, affects the maturation of human monocyte-derived dendritic cells. Maturation markers and intracellular signaling pathways were evaluated. YC-1 inhibited the lipopolysaccharide up-regulation of mature markers, including CD40, CD80 or CD86 in a concentration-dependent manner with IC(50) values of 4.6+/-0.4, 4.9+/-0.6 or 4.5+/-0.5 microM, respectively. YC-1, at a higher concentration, inhibited lipopolysaccharide-induced HLADR expression. These effects of YC-1 were not reversed by ODQ (10 microM), which is a soluble guanylate cyclase inhibitor, nor by KT5823 (1 microM), which is a PKG inhibitor. Additionally, YC-1 did not increase levels of cyclic nucleotides in dendritic cells, supporting the claim that YC-1 affects dendritic cells maturation in a cGMP-independent manner. YC-1, in a cGMP-independent manner, inhibited lipopolysaccharide-induced Akt activation, IkappaBalpha degradation and NF-kappaB translocation, all of which are associated with co-stimulatory molecules expression. YC-1 inhibited the capacity of dendritic cell to activate allogenic T cells with an IC(50) value of 1.2+/-0.3 microM. YC-1-treated dendritic cells have mature phenotypes that exhibit up-regulated CCR7, enhanced IL-10 release and low phagocytosis activity in the presence of lipopolysaccharide. In conclusion, YC-1 inhibited the lipopolysaccharide-induced co-stimulatory molecular expression of dendritic cells by inhibiting Akt activation, IkappaBalpha degradation and NF-kappaB translocation. These inhibitory effects on co-stimulatory molecules suppressed the capacity of dendritic cells to activate allogenic T cells. Additionally, YC-1 treated dendritic cells exhibit the up-regulation of CCR7, enhanced IL-10 release and the down-regulation of phagocytosis in the presence of lipopolysaccharide. Accordingly, YC-1 might be a useful tool for evaluation of dendritic cells on autoimmune or allergic disease.
Graduate Institute of Natural Products, Chang Gung Medical College and University, No. 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan, 333 Taiwan, ROC.
I-Fang
IF
Tsai
Chun-Yen
CY
Lin
Ching-Tai
CT
Huang
Yung-Chang
YC
Lin
Choun-Mao
CM
Yang
Yin-Chou
YC
Lin
Chang-Hui
CH
Liao
D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000242:Cyclic AMP / Q000276:immunology; D006152:Cyclic GMP / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects*; D006162:Guanylate Cyclase; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D007191:Indazoles / Q000494:pharmacology*; D016753:Interleukin-10 / Q000276:immunology; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology; D009000:Monocytes / Q000166:cytology; D016328:NF-kappa B / Q000276:immunology; D010766:Phosphorylation / Q000187:drug effects; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000276:immunology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D000071756:Soluble Guanylyl Cyclase; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
C515370:CCR7 protein, human; D007155:Immunologic Factors; D007191:Indazoles; D016328:NF-kappa B; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D018160:Receptors, Cytoplasmic and Nuclear; D016753:Interleukin-10; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D000242:Cyclic AMP; D020928:Mitogen-Activated Protein Kinases; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP