Histamine Blocks Interleukin 2 (IL-2) Gene Expression and Regulates IL-2 Receptor Expression

Abstract

Histamine inhibited the proliferative response of human peripheral blood mononuclear cells (PBMC) to the T cell mitogen Phytohemagglutinin-P (PHA-P) in a dose-dependent fashion. This inhibition was mediated via the H2 receptor since cimetidine, a known H2 antagonist, removed the inhibition, whereas the addition of the H1 antagonist Diphenhydramine did not. Inhibition occurred during the inductive phase of the cell cycle, since histamine added 24 hours after PHA-P stimulation had no effect on subsequent T cell proliferation, and was attributable to inhibition of interleukin-2 (IL-2) gene expression. Both secreted IL-2 and messenger RNA coding for IL-2 were inhibited by histamine. In contrast, histamine exerted no inhibitory effect on the expression of cell surface receptors for IL-2 as determined by flow cytometry. Furthermore, histamine-treated cells retained full responsiveness to exogenously administered IL-2, which completely reversed the anti-proliferative effect of histamine. In some donors, histamine enhanced the percentage of IL-2 receptor positive cells. Stimulated PBMC from AIDS KS patients as a group, displayed a lower percentage of IL-2 receptor bearing cells, which was significantly increased by the addition of histamine even at concentrations as low as 10(-6) M and peaking at 10(-3) M. These findings indicate that histamine exerts its anti-proliferative effects on T cells by inhibiting IL-2 production, via blockade of IL-2 gene expression. In addition, histamine seems to exert immunomodulating effects on IL-2 receptor expression, particularly in those individuals with AIDS-KS.

Histamine Receptors on Lymphocytes: Distribution and Functional Significance

“…These data suggest that modulation of lymphocyte functions may occur via engagement of the H 1 R under physiological conditions. In contrast, several investigators reported in vitro modulation of lymphocyte functions, like inhibition of mitogen-induced proliferation [31][32][33] or cytokine production [34,35] following activation of the H 2 R.…”

“…Histamine inhibited mRNA expression and secretion of IL-2 at an early phase of T cell activation. Furthermore, no inhibition of IL-2 receptor expression could be found, and exogenous IL-2 reversed the antiproliferative effect of histamine [34].…”

Bidirectional communication between histamine and cytokines

“…On the other hand, histamine inhibited the phytohemagglutinin stimulation of human peripheral T-cells in the early phase by decreasing the expression of IL-2, acting via H2 receptors. The expression of IL-2 receptors was unchanged or even elevated, and exogenous IL-2 could prevent this inhibitory effect demonstrating that IL-2 sensitivity was unaltered [14]. In various subsets of CD4 + human T-cells histamine reduces the production of IL-2 and IFN-g [15], but there are also data about IFN-ginducing effects of histamine as well (in human T-cell clones isolated from airways (bronchoalveolar lavage fluid (BAL)) and blood) [16].…”

Cimetidine inhibits nitric oxide associated nitrate production in a soft‐tissue inflammation model in the horse

“…Cimetidine (CIM) and other antagonists have been used for many years to control gastric acid secretion in humans and in domestic species. It has been shown that at least two of the compounds in this class, CIM and ranitidine, bind to the heme‐iron portion of CYP (Rendic? et al ., 1984) to inhibit CYP activity, producing a decrease in the biotransformation of various xenobiotics which are metabolized by the CYP monooxygenases (Rendic?…”

“…It has been shown that at least two of the compounds in this class, CIM and ranitidine, bind to the heme‐iron portion of CYP (Rendic? et al ., 1984) to inhibit CYP activity, producing a decrease in the biotransformation of various xenobiotics which are metabolized by the CYP monooxygenases (Rendic? et al ., 1984; Ioannoni et al ., 1986).…”