Suppression of interleukin-12 production through endogenously secreted interleukin-10 in activated dendritic cells: involvement of activation of extracellular signal-regulated protein kinase.
Our recent study suggested the reverse relationship between the production of interleukin-10 (IL-10) and IL-12 in dendritic cells (DCs) activated by lipopolysaccharide (LPS) or LPS plus interferon (IFN)-gamma. In the present study, a series of experiments were performed to investigate the mechanisms responsible for this reverse relationship. Our results showed that neutralization of the secreted IL-10 by antibody could enhance the production of IL-12. Neutralization of IL-12 by antibody did not affect the IL-10 production. Addition of exogenous IL-10 suppressed the production of IL-12 by activated DCs, and addition of exogenous IL-12 did not affect IL-10 production. TaqMan real-time reverse transcriptase-polymerase chain reaction supported the fact that the observed effects occurred at mRNA transcription level. We also found that LPS or LPS plus IFN-gamma significantly enhanced the phosphorylation of extracellular signal-regulated protein kinase (ERK) and p38 mitogen-activated protein kinase. In addition, inhibition of ERK by PD98059 significantly suppressed IL-10 and increased the IL-12 production. Exogenous IL-10 reversed the upregulated production of IL-12 induced by PD98059. The above findings suggest a unidirectional negative autocrine regulation of IL-12 by IL-10 in activated DCs and that activation of ERK involves the differential production of IL-10 and IL-12 by activated DCs. Thus, the regulation of differential production of IL-10 and IL-12 may play an important role for DCs in priming T helper 1 (Th1) or Th2 in the immune responses.
Xia
C-Q
CQ
Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, USA.
Kao
K J
KJ
D003713:Dendritic Cells / Q000502:physiology*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000502:physiology*; D018664:Interleukin-12 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D048051:p38 Mitogen-Activated Protein Kinases
D005419:Flavonoids; D008070:Lipopolysaccharides; D016328:NF-kappa B; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one