DUAL CONTROL OF HUMAN INTERLEUKIN-2 AND INTERFERON-GAMMA GENE-EXPRESSION BY HISTAMINE - ACTIVATION AND SUPPRESSION

Histamine is considered to be an activator of cells with suppressive c apacity. In agreement with this concept, we show that histamine elicit s a strong inhibition of the induced expression of interleukin-a (IL-2 ) and interferon-gamma (IFN-gamma) genes. However, our experiments rev eal a novel property of histamine: early in the induction process, it strongly stimulates expression of these two genes in cultured human pe ripheral blood mononuclear cells (PBMC). The histamine-mediated superi nduction of IL-2 mRNA is seen also in a Th cell line, showing that suc h cells respond directly to histamine, In the course of mitogenic indu ction, a 20-fold stimulation by histamine is converted into an equally strong inhibition. The response of a PBMC population to histamine thu s undergoes a remarkable change following T cell activation. The dual effect of histamine can be blocked by the H2 histamine receptor antago nist cimetidine, while the early activation by histamine is mimicked b y the H2 agonist impromidine, showing that both activation and inhibit ion of IL-2 and INF-gamma gene expression by histamine are exerted via this receptor. These results support the concept that histamine, rele ased during an immune response, exerts opposite regulatory effects by first activating cells able to express the IL-2 and IFN-gamma genes an d only then suppressive cells that become responsive to histamine more slowly, but once activated shut off the expression of these genes. (C ) 1996 Academic Press, Inc.