Decreased sensitivity to cAMP in the in vitro generation of memory splenic cytotoxic T-lymphocytes from aged mice: role of phosphodiesterase.
The effects of increased intracellular concentration of cyclic AMP (cAMP) on cellular immune function of young and aged mice were examined by using an in vitro anti-influenza cytotoxic T-lymphocyte (CTL) assay. We found that increasing intracellular concentrations of cAMP with either the cAMP analog, N,6O2'-dibutyryl cAMP, or the beta adrenergic agonist, metaproterenol, significantly inhibited the in vitro development of memory CTL activity of young mice. The development of CTL activity of aged mice, however, was less sensitive to the effects of these agents. We found that the S-isomer of cAMPS, a cAMP analog resistant to the effects of PDE, caused equivalent inhibition of CTL activity in the young and aged mice. This suggested that the cause of the decreased cAMP sensitivity in aging was increased PDE activity. In subsequent experiments, we found that the PDE from T-cells of aged mice have higher KM and higher Vmax for cAMP than the PDE from T-cells of young mice. Because beta-agonists probably act as a counter-regulatory hormone at an inflammatory site, the decreased sensitivity to cAMP in aging may be a compensatory response to the age-related decline in immune function.
Bender
B S
BS
Department of Medicine, University of Florida College of Medicine.
Bell
W E
WE
Taylor
S
S
Scarpace
P J
PJ
D000375:Aging / Q000276:immunology*; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000494:pharmacology*; D005260:Female; D007156:Immunologic Memory; D009921:Metaproterenol / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D010727:Phosphoric Diester Hydrolases / Q000502:physiology*; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology
D011943:Receptors, Adrenergic, beta; D009921:Metaproterenol; D003994:Bucladesine; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases