EFFECTS OF LYMPHOKINES AND MITOGENS ON A HISTAMINE DERIVATIVE-INDUCEDINTRACELLULAR CALCIUM MOBILIZATION AND INOSITOL PHOSPHATE PRODUCTION

Histamine trifluoromethyl-toluidide derivative (HTMT), a novel immunos uppressive agent, stimulates H-1, H-2 and HTMT receptors in lymphocyte s. HTMT receptors are different from the classical H-1, H-2 or H-3 rec eptors. Stimulation of HTMT receptors results in increased intracellul ar concentrations of calcium ([Ca2+](i)) and inositol phosphate (IP) i n human peripheral blood lymphocytes. In the present study, we investi gated the effects of lymphokines [interleukin-4 (IL-4), interleukin-2 (IL-2)] and other pharmacologic agents [lipopolysaccharide (LPS), phor bol 12-myristate 13-acetate (PMA)] on HTMT-induced Ca2+ and IP respons es in non-rosetted cells. HTMT caused enhanced [Ca2+](i) and IP respon ses when the cells were pretreated with IL-4. The effects of IL-4 were concentration dependent and became maximal after the cells were incub ated 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 Ca2+ mobilization induced by HTMT. However, the effects of LPS were not altered by inhibitors of either protein synthesis or RNA transcription. This indicated that LP S may act differently than IL-4 on the HTMT response. IL-2 and PMA did not affect HTMT-induced [Ca2+](i) and IP responses. The effects of IL -4 and LPS were agonist specific. They did not affect the Ca2+ mobiliz ation 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 i mmune and/or inflammatory regulation.