Increased interleukin-4 production by atopic mononuclear leukocytes correlates with increased cyclic adenosine monophosphate-phosphodiesterase activity and is reversible by phosphodiesterase inhibition.
Previous studies have shown that leukocytes from patients with atopic dermatitis have increased levels of cyclic adenosine monophosphate (cAMP)-phosphodiesterase activity. This increased activity accounts for subnormal cAMP responses and correlates with increased in vitro immunoglobulin E production. To better understand the mechanism of this effect, we studied the relationship between phosphodiesterase activity and interleukin-4, a T-cell-derived cytokine that is a major regulator of immunoglobulin E production. Cultures stimulated with anti-CD3 or with phorbol myristate acetate plus ionophore significantly increased interleukin-4 production, and levels were consistently highest in cells from atopic subjects. Interleukin-4 production was higher, on a per T-cell basis, in mononuclear leukocyte cultures than in cultures of pure T cells, suggesting the possibility of a monocyte factor acting to increase interleukin-4 production. We next examined the effect of the phosphodiesterase inhibitor Ro 20-1724 on interleukin-4 production and found a significant reduction in cultures of atopic mononuclear leukocytes. This phosphodiesterase inhibitor effect appeared to act primarily on monocytes and correlated with increased intracellular cAMP levels. These studies demonstrate increased interleukin-4 production by atopic T cells. This abnormality can be reversed by inhibition of cAMP-phosphodiesterase, suggesting a possible therapeutic target for control of atopic disease.
Department of Dermatology, Oregon Health Sciences University, Portland 97201-3098.
S C
SC
Chan
S H
SH
Li
J M
JM
Hanifin
D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology; D000328:Adult; D000242:Cyclic AMP / Q000378:metabolism*; D003876:Dermatitis, Atopic / Q000378:metabolism*; D006801:Humans; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D009000:Monocytes / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D012016:Reference Values
D010726:Phosphodiesterase Inhibitors; D015847:Interleukin-4; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases