1 We have investigated the suppressive e ects of rolipram, RP 73401 (piclamilast) and other structurally diverse inhibitors of cyclic AMP-speci®c phosphodiesterase 4 (PDE4) on interleukin (IL)-2 generation from Balb/c mouse splenocytes exposed to the superantigen, Staphylococcocal enterotoxin-A (Staph. A). The purpose was to determine whether their potencies are more closely correlated with inhibition of PDE4 from CTLL cells, against which rolipram displays weak potency (low-a nity PDE4), or displacement of [ 3 H]-(+)-rolipram from its high-a nity binding site (HARBS) in mouse brain cytosol. 2 RP 73401 (IC 50 0.46+0.07 nM, n=4) was a very potent inhibitor of Staph. A-induced IL-2 release from Balb/c mouse splenocytes, being 41100 fold more potent than (+)-rolipram (IC 50 540+67 nM, n=3). 3 A close correlation (r=0.95) was observed between suppression of IL-2 release by PDE inhibitors and inhibition of PDE4. In contrast, little correlation (r=0.39) was observed between suppression of IL-2 release and their a nities for the high-a nity rolipram binding site (HARBS). 4 RP 73401 only inhibited partially (30 ± 40%) Staph. A-induced incorporation of [ 3 H]-thymidine into splenocyte DNA. The PDE3 inhibitor, siguazodan (10 mM), had little or no e ect on IL-2 release or DNA synthesis. This concentration of siguazodan did not enhance the inhibitory action of RP 73401 on IL-2 release but potentiated its e ect on DNA synthesis, increasing potency and e cacy. 5 Staph. A-induced DNA synthesis was only partially inhibited by anti-IL-2 neutralizing antibody, whereas dexamethazone (100 nM) and cyclosporine A (100 nM) completely blocked the response. 6 RP 73401 (IC 50 6.3+1.9 nM, n=4) was 140 fold more potent than rolipram (IC 50 900+300 nM, n=3) in inhibiting Staph. A-induced [ 3 H]-thymidine incorporation into splenocyte DNA. 7 The results implicate a low-a nity form of PDE4 in the suppression of Staph. A-induced IL-2 release from murine splenocytes by PDE inhibitors. The data also indicate that mitogenic factors other than IL-2, whose elaboration or responses to which are regulated by PDE3 as well as PDE4, contribute to the superantigen-induced DNA synthesis.

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