Role of mitogen-activated protein kinase and PI3K pathways in the regulation of IL-12-family cytokines in dendritic cells and the generation of T H-responses

Eur Cytokine Netw. 2010 Dec;21(4):319-28. doi: 10.1684/ecn.2010.0219. Epub 2010 Nov 29.


Mitogen-activated protein kinases (MAPK) are targets for the immune-modulation of dendritic cells (DC). However, our knowledge of their role in the regulation of IL-12-family cytokines is limited. This study investigated the roles of p38, JNK, p44/42 and PI3K pathways in IL-12/23/27 production by human DC, and their impact on naïve T(H)-responses. We first identified TOP and UBC as robust DC housekeeping genes. Peak transcription of p35 and p40 occurred by 12h, p19 and p28 by 8h and EBI3 by 12-24h. Using selective antagonists, we showed that p38 was a positive regulator of IL-12, 23 and 27, JNK positively regulated IL-12 and IL-27, and inhibition of MEK1/2 had no marked effect. In contrast, the PI3K pathway markedly attenuated IL-23 responses and, to a lesser extent, IL-12, but not IL-27. To identify the role of these soluble factors, we co-stimulated naïve CD4+ T-cells in the presence of DC supernatant. The presence of mature DC supernatant induced not only strong IFNγ responses, but also IL-10 and IL-17A. Inhibition of p38 ablated T(H1), and IL-10 and IL-17A responses, whilst modestly enhancing IL-5 secretion. In contrast, inhibition of MEK1/2 abolished IL-17A production, whilst leaving other responses unaffected, whereas inhibition of JNK or PI3K had no discernable effect. In summary, we describe the expression of IL-12-family cytokines from DC and propose a modified model for their regulation. This study further clarifies the potential for therapeutic modulation through these mediators.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Dendritic Cells / enzymology
  • Dendritic Cells / metabolism*
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Gene Expression Regulation* / drug effects
  • Humans
  • Interleukin-12 / genetics
  • Interleukin-12 / metabolism*
  • Interleukin-23 / genetics
  • Interleukin-23 / metabolism
  • Interleukins / genetics
  • Interleukins / metabolism
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • Signal Transduction
  • T-Lymphocytes, Helper-Inducer / immunology*


  • Interleukin-23
  • Interleukins
  • MYDGF protein, human
  • Protein Kinase Inhibitors
  • Interleukin-12
  • Mitogen-Activated Protein Kinases