Suppression of anti-CD3-induced interleukin-4 and interleukin-5 release from splenocytes of Mesocestoides corti-infected BALB/c mice by phosphodiesterase 4 inhibitors.
We investigated the suppressive effects of rolipram, RP 73401 (piclamilast), and other structurally diverse inhibitors of adenosine 3'5'-cyclic monophosphate (cAMP)-specific phosphodiesterase (PDE4) on anti-CD3-stimulated interleukin (IL)-4 and IL-5 generation by splenocytes from BALB/c mice infected with Mesocestoides (M) corti. RP 73401 (IC40: 0.011 +/- 0.004 microM) was a very potent inhibitor of anti-CD3-induced IL-4 release, being approximately 40-fold more potent than (+/-)-rolipram (IC40: 0.43 +/- 0.09 microM). A maximal inhibition of 60-70% of the response was achieved at the top concentrations of RP 73401 (1 microM) and rolipram (100 microM). These PDE inhibitors also suppressed IL-5 generation over the same concentration ranges, but the maximal suppression achieved was only 30-40%. R-(-)-rolipram (IC40: 0.39 +/- 0.09 microM) was approximately 6-fold more potent than S-(+)- rolipram (IC40: 2.6 +/- 0.95 microM) in inhibiting IL-4 release. A close correlation (r2 = 0.82) was observed between suppression of IL-4 release by PDE inhibitors and inhibition of CTLL cell PDE4, a form against which R-(-)-rolipram displayed relatively weak inhibitory potency. A poorer correlation (r2 = 0.26) was observed between suppression of IL-4 release and affinities of cAMP PDE inhibitors for the high-affinity rolipram binding site in mouse brain membranes. The cGMP-inhibited PDE (PDE3) inhibitor, siguazodan, had little or no effect (IC40 > 100 microM) on anti-CD3-stimulated release of either IL-4 or IL-5 and did not significantly enhance the inhibitory action of RP 73401 on the release of either of these cytokines. Finally, RP 73401 (IC50: 0.41 +/- 0.19 nM) inhibited anti-CD3-stimulated DNA synthesis in splenocyte preparations from M. corti-infected mice and siguazodan (10 microM) had no effect on this response, either alone or in combination with the PDE4 inhibitor. The results show that PDE4 inhibitors suppress the release of Th2 cytokines from anti-CD3-stimulated murine spenocytes and that this effect is correlated with inhibition of a low-affinity PDE4 form.
Souness
J E
JE
Rhône-Poulenc Rorer Central Research, Dagenham Research Centre, Essex, UK. john.souness@rhone-poulenc.com
Houghton
C
C
Sardar
N
N
Withnall
M T
MT
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D017252:CD3 Complex / Q000276:immunology*; D002590:Cestode Infections / Q000201:enzymology / Q000276:immunology* / Q000469:parasitology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D015847:Interleukin-4 / Q000378:metabolism*; D015848:Interleukin-5 / Q000378:metabolism*; D008645:Mesocestoides / Q000276:immunology* / Q000472:pathogenicity; D051379:Mice; D008807:Mice, Inbred BALB C; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology
D001549:Benzamides; D017252:CD3 Complex; D015848:Interleukin-5; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D015847:Interleukin-4; D004247:DNA; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C087566:piclamilast