Histamine up-regulates phosphodiesterase IV activity in U-937 cells through H2 receptor stimulation and cAMP increase.
BACKGROUND
An increase of phosphodiesterase 4 (PDE4) has been described in blood mononuclear white cells of patients with atopic dermatitis (AD). This study was intended to search for the putative relationship between histamine and PDE4 in inflammatory cells.


METHODS
The human monocyte cell line U-937 was used as a model of blood mononuclear leucocytes. PDE4 activity was determined as the increase of cAMP degradation, which is specifically inhibited by rolipram. Intracellular cAMP content was measured and correlated to PDE4 activity.


RESULTS
1 microM histamine produced a 2- to 3-fold selective increase in PDE4 activity in U-937 cells after 4 hours of incubation. Enzyme activation was reversible, concentration- and time dependent. Cycloheximide (10 microM) prevented histamine-induced stimulation of PDE4. The H2-receptor antagonist, ranitidine, but not the H1-receptor antagonist, diphenhydramine, prevented histamine-induced activation of PDE4 in a concentration-dependent manner. Inhibition of cAMP degradation in the presence of histamine plus rolipram after 4 h of incubation further increased cAMP levels and PDE4 activity.


CONCLUSIONS
These results suggest that histamine-induced stimulation of PDE4 is mediated by the H2 receptor and related to intracellular levels of cAMP. AMPc enhancement of the cyclic nucleotide levels may trigger expression and synthesis of this enzyme.
Delgado
Mercedes
M
Departamento de Farmacolog a, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain. mwallace@pluri.ucm.es
Fuentes
José A
JA
Fernandez-Alfonso
María S
MS
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004155:Diphenhydramine / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D006632:Histamine / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D011688:Purinones / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D011899:Ranitidine / Q000494:pharmacology; D011970:Receptors, Histamine H2 / Q000187:drug effects / Q000502:physiology*; D020889:Rolipram / Q000494:pharmacology; D020298:U937 Cells
D006146:Guanidines; D011688:Purinones; D011724:Pyridazines; D011970:Receptors, Histamine H2; C056215:siguazodan; D006632:Histamine; D011899:Ranitidine; D004155:Diphenhydramine; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C011145:zaprinast; D020889:Rolipram; D015056:1-Methyl-3-isobutylxanthine