Open Access

ARTICLE

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

Andrew M. Jackson^1,*, Lori A. Mulcahy^1,*, Joanne Porte², Hester A. Franks¹, Mohamed El Refaee¹, Qunwei Wang¹, Suharsh Shah¹, XingWu Zhu¹, Poulam M. Patel¹

1 Academic Unit of Clinical Oncology
2 Respitatory Medicine, University of Nottingham, City Hospital, Nottingham, UK

* Corresponding Author: A.M. Jackson,

European Cytokine Network 2010, 21(4), 319-328. https://doi.org/10.1684/ecn.2010.0219

Accepted 16 July 2010;

Abstract

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.

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