Histamine trifluoromethyl-toluidine derivative (HTMT), a novel immunosuppressive agent, stimulates H1, H2 and HTMT receptors in lymphocytes. HTMT receptors are different from the classical H1, H2 or H3 receptors. Stimulation of HTMT receptors results in increased intracellular concentrations of calcium ([Ca2+]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 Ca2+ and IP responses in non-rosetted cells. HTMT caused enhanced [Ca2+]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 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 LPS 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+ 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.