S. C. Chan

Heterologous desensitization of leukocytes: a possible mechanism of beta adrenergic blockade in atopic dermatitis

Studies of mononuclear leukocytes from patients with atopic dermatitis showed depressed cyclic AMP (cAMP) responses after exposure to isoproterenol, histamine, and prostaglandin E1. Because plasma and tissue histamine levels are elevated in atopic dermatitis, we questioned whether histamine or other mediators might be responsible for cAMP abnormalities. We found that exposure of normal cells to low (10(-6)M) concentrations of histamine, isoproterenol, or prostaglandin E desensitized the cells to subsequent stimulatory concentrations of any of the agonists. This heterologous desensitization occurred within 15 min and persisted for days, with gradual recovery of cAMP responses roughly paralleling those of cells from patients with atopic dermatitis. These findings provide a possible explanation for Szentivanyis beta adrenergic blockade theory and the depressed leukocyte cAMP response to multiple agonists in atopy.

Histamine induced elevation of cyclic AMP phosphodiesterase activity in human monocytes

We have previously reported histamine desensitization of human blood mononuclear leukocytes resulting in reduced cAMP responses to β-adrenergic agonists, histamine and prostaglandin E1. This heterologous desensitization occurred at low, micromolar histamine concentrations and was accompanied by elevation of cAMP-phosphodiesterase (PDE) activity in these cells. We have now investigated the activity of PDE in the lymphocyte and monocyte fractions of mononuclear leukocytes to determine the site of histamine effect.PDE activity per cell was higher in monocytes (0.075±0.070 units) than lymphocytes (0.026±0.08) units). Monocytes responded to 10−6M histamine stimulation with a much greater increase in PDE activity (0.354±0.1 units) than did lymphocytes (0.047±0.015 units). Histamine receptor studies, using thiazolylethylamine and chlorpheniramine as H1-agonist and antagonist respectively and dimaprit and cimetidine as H2-agonists and antagonists respectively, indicated that the histamine stimulation of PDE activity is mediated predominantly through H1 histamine receptor in the monocytes and the H2 receptor in the lymphocytes. Previously histamine had been thought to increase cyclic AMP by acting on H2 receptors to activate adenylate cyclase. Our studies show that stimulation of H1 or H2 receptors by low histamine concentration can cause the opposite effect i.e. increased catabolism and a net reduction in cAMP levels. The localization of this effect predominantly to monocytes indicates a potentially important mechanism for histamine action on immune regulation.

Elevated mononuclear leukocyte phosphodiesterase in allergic dogs with and without airway hyperresponsiveness

To investigate if mononuclear leukocyte beta-adrenergic hyporesponsiveness of Basenji greyhound (BG) dogs is associated with atopy or nonspecific airway hyperresponsiveness, we examined the relationship between mononuclear leukocyte cAMP phosphodiesterase levels, airway responsiveness to methacholine, and intradermal allergen responses in 17 BG dogs, five unrelated purebred Basenjis, and five greyhounds. BG dogs were hyperresponsive to aerosols of methacholine compared to Basenjis and greyhounds. Both BG dogs and Basenjis were allergic and had increased leukocyte cAMP phosphodiesterase activity compared to greyhounds. We concluded that the leukocyte abnormality is not associated with airway hyperresponsiveness. The leukocyte abnormality is either associated with the allergic state, with some hereditary trait that BG dogs acquired from the Basenji ancestry, or the leukocyte abnormality is necessary but not sufficient for the development of airway hyperresponsiveness.