RESPONSES OF HUMAN DERMAL MICROVASCULAR ENDOTHELIAL-CELLS TO HISTAMINE AND THEIR MODULATION BY INTERLEUKIN-1 AND SUBSTANCE-P

The action of histamine on human dermal microvascular endothelial cells and modulation of its effects by the cytokine interleukin-1 and the vasoactive neuropeptide substance P have been investigated. Histamine (10(-6)-10(-3) M) induces release of prostaglandin E2 in a concentration- and time-dependent manner. Prostaglandin E2 release is facilitated principally by histamine H-1 receptors as the H-1 receptor antagonist pyrilamine attenuates prostaglandin E2 release whereas the H-2 receptor antagonist cimetidine only slightly reduces release. In contrast to other cells, the histamine/receptor interaction is not associated with increased intracellular accumulation of the cyclic nucleotides, cyclic AMP, or cyclic GMP. Interleukin-1 induces a concentration-dependent release of prostaglandin E2 following 24 h incubation. However, substance P does not increase release of prostaglandin E2 above baseline. In cells incubated with 1 U/ml human recombinant interleukin 1-alpha for 24 h prior to stimulation with histamine (10(-5)-10(-3) M) for 30 min, there is a significant potentiation of histamine-induced release of prostaglandin E2 (p < 0.05). Using a solubilized cell sonicate prepared from human dermal microvascular endothelial cells incubated with 1 U/ml human recombinant interleukin 1-alpha for 24 h, conversion of exogenous arachidonic acid into prostaglandin E2 increased by 60.19 +/- 18.28%. Cycloheximide partially reduces the increased conversion but completely blocks interleukin-1-induced release of prostaglandin E2 from intact cells. Substance P does not potentiate histamine-induced release of prostaglandin E2 or increase arachidonic acid conversion. These results demonstrate that human dermal microvascular endothelial cells are responsive to histamine and that interleukin-1, but not substance P, can potentiate histamine-induced release of prostaglandin E2. Interleukin-1 appears to act, at least in part, by regulating the availability of free arachidonic acid. Interactions between histamine and interleukin-1 may be important in the modulation of inflammatory reactions in skin.