TY - EJOU
AU - Jackson, Andrew M.
AU - Mulcahy, Lori A.
AU - Porte, Joanne
AU - Franks, Hester A.
AU - Refaee, Mohamed El
AU - Wang, Qunwei
AU - Shah, Suharsh
AU - Zhu, XingWu
AU - Patel, Poulam M.
TI - Role of mitogen-activated protein kinase and PI3K pathways in the regulation of IL-12-family cytokines in dendritic cells and the generation of TH-responses
T2 - European Cytokine Network
PY - 2010
VL - 21
IS - 4
SN - 1952-4005
AB - Mitogen-activated protein kinases (MAPK) are targets for the immune-modulation of dendriticcells (DC). However, our knowledge of their role in the regulation of IL-12-family cytokines is limited. Thisstudy 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 TH-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 selectiveantagonists, we showed that p38 was a positive regulator of IL-12, 23 and 27, JNK positively regulated IL-12and IL-27, and inhibition of MEK1/2 had no marked effect. In contrast, the PI3K pathway markedly attenu-ated 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 superna-tant induced not only strong IFNγ responses, but also IL-10 and IL-17A. Inhibition of p38 ablated TH1, andIL-10 and IL-17A responses, whilst modestly enhancing IL-5 secretion. In contrast, inhibition of MEK1/2 abol-ished IL-17A production, whilst leaving other responses unaffected, whereas inhibition of JNK or PI3K had nodiscernable effect. In summary, we describe the expression of IL-12-family cytokines from DC and propose amodified model for their regulation. This study further clarifies the potential for therapeutic modulationthrough these mediators.
KW - dendritic cell
KW - IL-12
KW - IL-23
KW - IL-27
KW - signalling
KW - TH
DO - 10.1684/ecn.2010.0219