HISTAMINE INDUCED HOMOLOGOUS AND HETEROLOGOUS REGULATION OF HISTAMINE RECEPTOR SUBTYPE mRNA EXPRESSION IN CULTURED ENDOTHELIAL CELLS

Abstract

Histamine has been proposed to play an important role in early inflammatory responses, based on studies documenting the effects of histamine on vasodilation and permeability of microvascular endothelium, as well as histamine-stimulated neutrophil adhesion to endothelial cells. The complex and heterogeneous biological mechanisms of histamine-mediated responses are not yet completely characterized. One of the factors defining inflammatory responses stimulated by histamine might be the distribution and density of receptor subtypes on cell membranes. The aim of this study was to assess whether the regulation of histamine receptor mRNA levels represents a control point in histamine-stimulated processes. Histamine-induced regulation of histamine receptor subtype expression was studied in vitro by semiquantitative RT-PCR analysis of total RNA extracted from stimulated and unstimulated endothelial cells. The time dependency and extent of histamine induced down-regulation varied between the H1 and H2 receptor message. The rapid decrease of H2 receptor mRNA lasted for 24 h. On the other hand, the less-pronounced reduction of H1 mRNA was transient and returned to control values after 12 h of histamine stimulation. The H2 receptor message was mainly down-regulated by activation of the H1 receptor protein. Down-regulation of the H1 receptor message seemed to be a net result of H1 and H2 receptor activation. This is the first report demonstrating a complex pattern of homologous and heterologous regulation of histamine receptor expression. These findings reveal new insight into the potential diversity of the mechanism involved in processing information via stimulation of multiple G-protein-linked pathways.