Effect of phosphodiesterase inhibition on IL-4 and IL-5 production of the murine TH2-type T cell clone D10.G4.1.
The effect of various phosphodiesterase (PDE) inhibitors on anti-CD3 induced interleukin-(IL)-4 and IL-5 production of the murine T helper cell clone of type 2 phenotype D10.G4.1 (D10) has been investigated in vitro. D10 cells were incubated in the presence of drugs and anti-CD3 mAb for 16 h before measurement of cytokines in the cell supernatants by ELISA. Whereas all PDE inhibitors tested exerted minimal effects on anti-CD3 induced IL-4 production, a marked increase in IL-5 production by the non-selective PDE inhibitors IBMX, theophylline and enprofylline was observed. The action of these non-selective PDE inhibitors was mimicked by the PDE IV-selective inhibitor rolipram and in part by the PDE III-selective inhibitors motapizone and milrinone, whereas the PDE V-selective inhibitor zaprinast was inactive. Rolipram and motapizone enhanced IL-5 production in a synergistic fashion. In support of the functional importance of PDE III and IV for IL-5 synthesis in intact murine D10 cells, we have found PDE III and IV to be the predominant isoenzyme activities in corresponding cell lysates. The stimulatory effect of rolipram on IL-5 production was almost totally reversed by the protein kinase A inhibitor KT-5720. In addition, the membrane-permeable cAMP analogue 8-bromo-cAMP mimicked the stimulatory effect of PDE inhibitors on IL-5 production while leaving IL-4 levels unaffected. Both results support the view that the action of the PDE inhibitors on murine D10 cells is mediated via an elevation of intracellular cAMP.
Schmidt
J
J
ASTA Medica AG, Department of Pharmacology, Frankfurt/Main, Germany.
Hatzelmann
A
A
Fleissner
S
S
Heimann-Weitschat
I
I
Lindstaedt
R
R
Szelenyi
I
I
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D002478:Cells, Cultured; D002999:Clone Cells; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D015847:Interleukin-4 / Q000096:biosynthesis*; D015848:Interleukin-5 / Q000096:biosynthesis*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D051379:Mice; D008806:Mice, Inbred AKR; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology; D018418:Th2 Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D015848:Interleukin-5; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D015847:Interleukin-4; D015124:8-Bromo Cyclic Adenosine Monophosphate; C051270:motapizone; D017868:Cyclic AMP-Dependent Protein Kinases