Abstract

Histamine is known to trigger the release of interleukin (IL)-16 from human CD8⁺ cells. However, the individual roles of the presently known histamine receptor subtypes (H₁-H₄) in this inflammatory response have not been fully characterized. Histamine stimulation of human CD8⁺ T lymphocytes purified from peripheral blood led to a 5- to 8-fold increase in the basal release of IL-16 within 24 h, and this increase was significantly blocked by the H₂-selective antagonist, cimetidine, or by thioperamide, an antagonist of H₃ and H₄ receptors, respectively. The H₁ antagonist pyrilamine showed limited effects. Agonists selective for H₂ (dimaprit), H_3/4 (R-(−)-α-methylhistamine), and H₄ (clobenpropit) were capable of inducing the release of bioactive IL-16 because CD8⁺ cell supernatants induced CD4⁺ cell migration, which was abrogated by an anti-IL-16 antibody. Furthermore, preincubation of lymphocytes with pertussis toxin abolished IL-16 release triggered by activation of the G_i/o-coupled H₄ receptor but not by the H₂ receptor. Messenger RNA expression studies confirmed H₄, H₂, and H₁ expression in human CD8⁺ lymphocytes, whereas H₃ mRNA was completely absent. All leukocyte populations investigated expressed mRNA for H₄, with highest levels found in eosinophils, dendritic cells, and tonsil B cells. H₄ expression was also detected in human lung, trachea, and various cells of human lung origin, such as fibroblasts, bronchial smooth muscle cells, epithelial, and endothelial cells. Since many of those are known sources of IL-16, immune cell- and lung cell-expressed H₄ receptors may have a general role in the control of this mediator of inflammatory disorders such as asthma.