Relationship between increased cyclic AMP-phosphodiesterase activity and abnormal adenylyl cyclase regulation in leukocytes from patients with atopic dermatitis.
Atopic dermatitis (AD) is characterized by a variety of abnormal physiologic and pharmacologic responses in the skin. Leukocyte abnormalities of the cyclic nucleotide system include increased cAMP phosphodiesterase (PDE) and adenylyl cyclase activities. We have evaluated the possibility that a defect of the inhibitory GTP-binding protein (Gi) might cause inadequate modulation of adenylyl cyclase activity in AD leukocytes. We carried out a series of studies assessing adenylyl cyclase and Gi subunits in monocyte membranes. Using both pertussis toxin ribosylation and direct monoclonal antibody labeling of Gi proteins, we have shown evidence for a decrease or possible absence of one of the Gi proteins in atopic monocyte membranes. A genetic defect or toxin-mediated abnormality in leukocyte membrane Gi could account for these findings. Increased cAMP degradation by PDE may be a compensatory mechanism for increased cAMP synthesis that is regulated by GTP-binding proteins. But this increased PDE activity also rendered AD leukocytes hypo-responsive to immunofunction regulatory signals mediated by cAMP.
Hanifin
J M
JM
Oregon Health Sciences University, Portland 97201-3098.
Lloyd
R
R
Okubo
K
K
Guerin
L L
LL
Fancher
L
L
Chan
S C
SC
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000097:blood*; D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000097:blood*; D005576:Colforsin / Q000494:pharmacology; D003876:Dermatitis, Atopic / Q000097:blood / Q000201:enzymology*; D004591:Electrophoresis, Polyacrylamide Gel; D019204:GTP-Binding Proteins / Q000276:immunology; D006801:Humans; D015151:Immunoblotting; D007962:Leukocytes / Q000201:enzymology*; D037342:Pertussis Toxin; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D010566:Virulence Factors, Bordetella; D005576:Colforsin; D037342:Pertussis Toxin; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases