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

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.