Premium
Differential effect of phosphodiesterase 4 inhibitors on the proliferation of human peripheral blood mononuclear cells from normals and subjects with atopic dermatitis
Author(s) -
Banner Katharine H.,
Roberts Nerys M.,
Page Clive P.
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb15120.x
Subject(s) - peripheral blood mononuclear cell , atopic dermatitis , medicine , peripheral blood , immunology , phosphodiesterase , peripheral , pharmacology , dermatology , enzyme , biology , biochemistry , in vitro
1 The aims of this study were to compare the effects of selective inhibitors of the type 3, type 4 and type 5 phosphodiesterase (PDE) isoenzymes on the phytohaemagglutinin (PHA)‐stimulated proliferation of human peripheral blood mononuclear cells (HPBM) from normals and subjects with atopic dermatitits (AD). 2 Mononuclear cells were isolated from peripheral venous blood of normals and subjects with AD. A concentration‐response curve was carried out with PHA (0.5‐5 μg ml − ) and a concentration which produced a submaximal stimulation of proliferation (2 μg ml − ) was selected for further experiments. HPBM (10 5 cells per well) were stimulated with PHA (2 μg ml − ) in the absence or presence of PDE inhibitor (0.01 μ m − 10 μ m ) and 24 h later [ 3 H]‐thymidine (0.1 μCi per well) was added. Cells were incubated for an additional 24 h period and [ 3 H]‐thymidine incorporation measured. 3 The type 4 PDE inhibitors (rolipram, RO 20–1724 and denbufylline) produced a concentration‐related inhibition of proliferation of HPBM from normal and AD subjects. The IC 50 for rolipram was significantly ( P <0.05) lower in HPBM from AD patients 0.28 μ m (95% confidence limits (CL): 0.158‐0.499, n = 5) vs normal subjects 2.6 μ m (95% CL: 0.867‐7.05, n = 5, P < 0.05) as were the IC 50 values for denbufylline: 0.26 μ m (95% CL: 0.152‐0.440, n = 5) vs 1.84 μ m (95% CL: 0.467‐7.23, n = 5, P <0.05) respectively and RO 20–1724: 1.49 μ m (95% CL: 0.61 μ m ‐3.64 μ m ) vs 6.46 μ m (95% CL: 2.03 μ m ‐20.46 μ m ), respectively. 4 The mixed type 3/4 inhibitors (zardaverine and benzafentrine) produced a concentration‐related inhibition of proliferation of HPBM from normal and AD subjects. The IC 50 value for zardaverine in HPBM from normal subjects: 1.8 μ m (95% CL: 0.43 μ m − 7.85 μ m , n =4) was similar to that in AD subjects: 1.03 μ m (95% CL: 0.48 μ m −2.28 μ m ) as was the IC 50 value for benzafentrine in normal 3.8 μ m (95% CL: 2.45 μ m − 5.9 μ m ) and atopic 5.5 μ m (95% CL: 3.84 μ m − 7.78 μ m ) HPBM. The type 5 PDE inhibitor, zaprinast was ineffective at inhibiting the proliferation of normal HPBM. The type 3 PDE inhibitor, siguazodan only inhibited [ 3 H]‐thymidine incorporation at a concentration of 10 μ m . 5 These results show that combined inhibition of the type 3 and 4 PDE isoenzymes in HPBM from normal subjects has a greater antiproliferative effect than inhibition of the type 4 isoenzyme alone. In addition these data indicate that the proliferative response of HPBM from AD subjects is more sensitive to PDE 4 inhibition than the proliferation of HPBM from normals.