Effects of lymphokines and mitogens on a histamine derivative-induced intracellular calcium mobilization and inositol phosphate production

Abstract

Histamine trifluoromethyl-toluidide derivative (HTMT), a novel imrnunosuppressive agent, stimulates H 1, H 2 and HTMT receptors in lymphocytes. HTMT receptors are different from the classical H 2, H 2 or H 3 receptors. Stimulation of HTMT receptors results in increased intracellular concentrations of calcium ([Ca 2+] i) and inositol phosphate (IP) in human peripheral blood lymphocytes. In the present study, we investigated the effects of lymphokines [interleukin-4 (IL-4), interleukin-2 (IL-2)] and other pharmacologic agents [lipopolysaccharide (LPS), phorbol 12-myristate 13-acetate (PMA)] on HTMT-induced Ca 2+ and IP responses in non-rosetted cells. HTMT caused enhanced [Ca 2+] i and IP responses when the cells were pretreated with IL-4. The effects of IL-4 were concentration dependent and became maximal after the cells were incubated with IL-4 for 48 hr. Inhibitors of protein synthesis, but not of RNA synthesis, blocked the effects of IL-4 on HTMT-induced responses. LPS was more potent than IL-4 in augmenting Ca 2+ mobilization induced by HTMT. However, the effects of LPS were not altered by inhibitors of either protein synthesis or RNA transcription. This indicated that LPS may act differently than IL-4 on the HTMT response. IL-2 and PMA did not affect HTMT-induced [Ca 2+] i and IP responses. The effects of IL-4 and LPS were agonist specific. They did not affect the Ca 2+ mobilization induced by PAF. The data indicate that the response to HTMT can be regulated by IL-4 and LPS. Although the in vivo importance of these receptors is not yet clear, the receptor is likely a contributor to immune and/or inflammatory regulation.