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Vol. 303, Issue 1, 300-307, October 2002

Histamine H4 and H2 Receptors Control Histamine-Induced Interleukin-16 Release from Human CD8+ T Cells

Florian Gantner, Katsuya Sakai, Michael W. Tusche, William W. Cruikshank1, David M. Center1 and Kevin B. Bacon

Bayer Yakuhin, Ltd., Research Center Kyoto, Therapeutic Research Area Asthma, Japan

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), H3/4 (R-(-)-alpha -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 Gi/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.

1 Current address: Pulmonary Center, Boston University School of Medicine, Boston, MA.

0022-3565/02/3031-0300$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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