TY - JOUR
T1 - Interferons modulate FcεRI-dependent production of autoregulatory IL-10 by circulating human monocytoid dendritic cells
AU - Le, Trong
AU - Tversky, Jody
AU - Chichester, Kristin L.
AU - Bieneman, Anja P.
AU - Huang, Shau Ku
AU - Wood, Robert A.
AU - Schroeder, John T.
PY - 2009/1
Y1 - 2009/1
N2 - Background: Immature human blood monocytoid dendritic cells (mDCs) express high-affinity receptors for IgE (FcεRI), yet their exact function and regulation remain poorly understood. Objective: We sought to characterize FcεRI-dependent cytokine responses and their regulation in circulating human blood mDCs. Methods: FcεRI-dependent cytokine responses of circulating mDCs were studied by using anti-FcεRIα stimulation. Plasmacytoid dendritic cell (pDC) cross-regulation through Toll-like receptor 9 on these responses was investigated by examining the effects of exogenous IFN-α pretreatment and by coculturing pDCs and mDCs stimulated with CpG. Culture supernatants were analyzed by means of ELISA to determine cytokine levels. Cell markers were determined by means of flow cytometry. Results: mDCs express marked levels of FcεRI (net mean fluorescence intensity, 196 ± 49; n = 4). After FcεRI-dependent activation in mDCs, TNF-α (2189 ± 864 pg/106 mDCs, n = 3) levels were upregulated within 4 hours, whereas IL-10 (112 ± 47 pg/106 mDCs, n = 3) levels were detectable only after 24 hours of incubation. After adding IL-10-neutralizing antibody, TNF-α FcεRI-dependent responses were significantly augmented (3903 ± 197 pg/106 mDCs, P < .01, n = 3). Conversely, recombinant IL-10 dose-dependently inhibited FcεRI-mediated TNF-α responses up to 86% ± 3% (n = 3, P < .001). Pretreatment of mDCs with IFN-α (100 U/mL) enhanced FcεRI-dependent secretion of IL-10 by 3.2-fold (183 ± 11 pg/106 mDCs, n = 4) compared with that seen in untreated cells (57 ± 33 pg/106 mDCs, P < .001, n = 4). In pDC/mDC cocultures pretreated with CpG, FcεRI-dependent IL-10 secretion by mDCs was similarly augmented by 3-fold. Conclusions: Autocrine secretion of IL-10, a critical autoregulator of FcεRI-dependent proinflammatory responses in mDCs, is cross-regulated by IFN-α, a major product of Toll-like receptor 9 responses in pDCs that normally promotes TH1 immunity.
AB - Background: Immature human blood monocytoid dendritic cells (mDCs) express high-affinity receptors for IgE (FcεRI), yet their exact function and regulation remain poorly understood. Objective: We sought to characterize FcεRI-dependent cytokine responses and their regulation in circulating human blood mDCs. Methods: FcεRI-dependent cytokine responses of circulating mDCs were studied by using anti-FcεRIα stimulation. Plasmacytoid dendritic cell (pDC) cross-regulation through Toll-like receptor 9 on these responses was investigated by examining the effects of exogenous IFN-α pretreatment and by coculturing pDCs and mDCs stimulated with CpG. Culture supernatants were analyzed by means of ELISA to determine cytokine levels. Cell markers were determined by means of flow cytometry. Results: mDCs express marked levels of FcεRI (net mean fluorescence intensity, 196 ± 49; n = 4). After FcεRI-dependent activation in mDCs, TNF-α (2189 ± 864 pg/106 mDCs, n = 3) levels were upregulated within 4 hours, whereas IL-10 (112 ± 47 pg/106 mDCs, n = 3) levels were detectable only after 24 hours of incubation. After adding IL-10-neutralizing antibody, TNF-α FcεRI-dependent responses were significantly augmented (3903 ± 197 pg/106 mDCs, P < .01, n = 3). Conversely, recombinant IL-10 dose-dependently inhibited FcεRI-mediated TNF-α responses up to 86% ± 3% (n = 3, P < .001). Pretreatment of mDCs with IFN-α (100 U/mL) enhanced FcεRI-dependent secretion of IL-10 by 3.2-fold (183 ± 11 pg/106 mDCs, n = 4) compared with that seen in untreated cells (57 ± 33 pg/106 mDCs, P < .001, n = 4). In pDC/mDC cocultures pretreated with CpG, FcεRI-dependent IL-10 secretion by mDCs was similarly augmented by 3-fold. Conclusions: Autocrine secretion of IL-10, a critical autoregulator of FcεRI-dependent proinflammatory responses in mDCs, is cross-regulated by IFN-α, a major product of Toll-like receptor 9 responses in pDCs that normally promotes TH1 immunity.
KW - Dendritic cells
KW - FcεRI
KW - IFN-α
KW - IL-10
KW - TNF-α
UR - http://www.scopus.com/inward/record.url?scp=58149105644&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=58149105644&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2008.09.013
DO - 10.1016/j.jaci.2008.09.013
M3 - Article
C2 - 18845324
AN - SCOPUS:58149105644
SN - 0091-6749
VL - 123
SP - 217
EP - 223
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 1
ER -