Combination use of immune complexes and a Ca2+ channel blocker azelnidipine enhances interleukin-12 p40 secretion without T helper type 17 cytokine secretion in human monocyte-derived dendritic cells

Abstract

Summary Immune complexes (ICs) improve the capacity of priming specific CD8+ cytotoxic T cell responses of dendritic cells (DCs). ICs induce phosphorylation of mitogen-activated protein kinases (MAPK) and calcium influx, although the precise regulating mechanism still remains unclear. In the present study, we investigated the effect of a Ca2+ channel blocker on the phosphorylation of p38 MAPK and extracellular signal-regulated kinase (ERK) in immature monocyte-derived DCs stimulated with lipopolysaccharide (LPS) or LPS-ICs, and the production of interleukin (IL)-12 family members (p40, p70, IL-23), T helper type 17 (Th17) cytokines (IL-6 and IL-23), tumour necrosis factor (TNF)-α and IL-10 were also investigated. In comparison with LPS stimulation, LPS-ICs stimulation enhanced p38 MAPK phosphorylation significantly, which was associated with an increase in IL-12 p40 monomer/homodimer secretion. LPS-ICs also enhanced TNF-α and IL-6 secretion, but suppressed IL-23 secretion. The use of azelnidipine (Aze), a long-acting L-type Ca2+ channel blocker with a high lipid solubility, suppressed p38 MAPK phosphorylation stimulated with LPS or LPS-ICs, but surprisingly enhanced IL-12 p40 monomer/homodimer secretion stimulated with LPS-ICs. This IL-12 p40 secretion-enhancing effect was not accompanied by IL-10 or IL-23 production, but was associated with ERK phosphorylation. The use of Aze did not affect IL-12 p70 production. These results suggest that the use of Aze enhances ICs-mediated IL-12 p40 secretion without additional IL-23 secretion. Therefore, the use of Aze and ICs could be a new therapeutic approach to immunomolecular therapy, as it does not cause Th17 differentiation which induces autoimmunity or reduces anti-tumour immunity.