Impact of an H3/4 Receptor Antagonist on Chemokine and Cytokine Synthesis By PBMC and Dendritic Cells Derived from PBMC

Rationale: Histamine H₃ and H₄ histamine receptors are involved in immune modulation. Peripheral blood mononuclear cells (PBMC) and dendritic cells (DCs) derived from PBMC synthesize cytokines and chemokines which may be modulated by blockade of H_3/ H₄ histamine receptors.

Methods: PBMC and DCs derived from 10 healthy donors were cultivated in the presence of dual H3/4 histamine receptor antagonist Ciproxifan (10^-5M). The concentrations of cytokines and chemokines in 48-hour cultures were assessed by Multiplex assays using Luminex xMAP technology.

Results: Cultivation of PBMC with the H_3/4 antagonist significantly increased  secretion of IL-4, IL-13, IL-18, IL-27, IL1a and IP-10 (p<0.05) and inhibited secretion of multiple chemo- and cytokines,  SCF, GM-CSF, LIF, IL-2, -5, -6, -7, -9, -15, -31.  In DC culture Ciproxifan significantly up-regulate the secretion of SCF, GM-CSF, IL1-α and IL-5 and down-regulates the production of IL-2, IL-6, IL-15 and LIF (p<0.05). Ciproxifan increases secretion of chemokines by PBMC (Eotaxin, RANTES, MIP-1α, MIP-1β) as well as DC (MCP-1 and RANTES).

Conclusions: Histamine H_3/4  receptors are involved in the regulation of secretion of cytokines and chemokines by both PBMC and DC derived from PBMC.