IFN-gamma activated JAK-1 shifts CD40-induced cytokine profiles in human antigen-presenting cells toward high IL-12p70 and low IL-10 production

Michael Conzelmann (1, 2) , Andreas H. Wagner (3) , Anke Hildebrandt (3) , Elena Rodionova (1, 2) , Michael Hess (1, 2) , Annika Zota (1) , Thomas Giese (3) , Christine S. Falk (3) , Markus Hecker (3) , Anthony D. Ho (2) , Peter Dreger (2) , Thomas Luft (1, 2)

1 Department of Molecular Oncology/Hematology
2 Department of Medicine V
3 Universität Heidelberg [Heidelberg] = Heidelberg University

CD40Ligand (CD40L) represents a strong endogenous danger signal associated with chronic inflammatory disease. CD40L induces activation of antigen-presenting cells (APC) such as DCs, monocytes, B-cells and endothelial cells. However, CD40 activation alone, whilst inducing IL-10 production, is insufficient to induce interleukin (IL)-12p70 release in human APCs suggesting that additional cytokine signals (e.g. GM-CSF, IL-4 or IFN-γ) are required for the induction of a pro-inflammatory cytokine profile. We demonstrate that IFN-γ-induced Janus kinase 1 (JAK1) enhances CD40-induced IL-12p70 release whilst simultaneously inhibiting IL-10 synthesis, resulting in a pro-inflammatory phenotype of CD40L-activated dendritic cells (DCs). JAK2 mediated enhancing effects on IL-12p70 but did not inhibit IL-10 release, whereas Tyk2 mediated inhibitory effects on IL-12p70 release in this system.

Mots clés: Dendritic cells; monocytes; B-cells; endothelial cells; CD40; CD40L; JAK; Tyk2; STAT; NF-κB; IRF-1; IRF-8; IL-12; IL-10

Michael Conzelmann, Andreas H. Wagner, Anke Hildebrandt, Elena Rodionova, Michael Hess, et al.. IFN-gamma activated JAK-1 shifts CD40-induced cytokine profiles in human antigen-presenting cells toward high IL-12p70 and low IL-10 production. Biochemical Pharmacology, 2010, 80 (12), pp.2074. ⟨10.1016/j.bcp.2010.07.040⟩. ⟨hal-00637155⟩