Effect of the carbocyclic nucleoside analogue MDL 201,112 on inhibition of interferon-γ-induced priming of Lewis (LEW/N) rat macrophages for enhanced respiratory burst and MHC class II Ia+ antigen expression

The effects of the carbocyclic nucbeoside MDL 201,112 and the purine nucleoside adenosine on the interferon-'y (IFN-'y)-induced priming of macrophages (ms) for the respiratory burst and major histocompati- bility class II (MHC class II) Iaantigen expression were compared. Priming of purified, peritoneal ms from Lewis (LEW/N) rats for 18 h with recombinant rat IFN-'y (rRaIFN--y) in the presence of either adenosine (100 �M) or MDL 201,112 (10 �M) resulted in a fourfold decrease in superoxide anion (02) production after stimulation with opsonized zymosan. Both agents were effective even when added 2 or 4 h after rRaIFN-y treatment. Peritoneal ms from LEW/N rats stimulated with LPS/ rRaIFN-'y were observed to secrete immunoreactive and bioactive TNF-a over 18 h in vitro and this cytokine could be dose-dependently inhibited by MDL 201,112. MDL 201,112 did not bind to classical A1 or A2 receptors on rat brain homogenates. Physiological levels of adeno- sine deaminase, or treatment with the nucleoside trans- port inhibitor dipyridamole, reversed the effects of adenosine; however, these agents at physiological concen- trations had little or no effect on the inhibition of 02 release mediated by MDL 201,112. Furthermore, incuba- tion of LEW/N m4s for 18 h in vitro with rRaIFN-y resulted in significant enhancement of MHC class II Ia� antigen expression, and these levels could be blocked by nearly 50% by either MDL 201,112 (10 �tM) or adenosine (100 �tM). MDL 201,112 and adenosine were also effective in decreasing mopsonized zymosan-stimulated #{176}2 levels and MHC class II Iaantigen expression in vivo. The effects of MDL 201,112 on the down-regulation of heat-killed M. tuberculosis-activated LEW/N mMHC class II Iaantigen expression in vitro appear to be medi- ated by a novel pathway, because there was no rank order of potency of ADO A1 or A2 agonist/antagonists (CCPA, NECA, XAC, or CPT) in our in vitro system. In sum- mary, our data provide compelling evidence that im- munoregubatory carbocyclic nucleoside analogues such as MDL 201,112 or adenosine appear to regulate LEW/N rat mactivation through novel molecular mechanisms and may have important therapeutic implications for acute and chronic inflammatory diseases. J. Leukoc. Biol. 56: 133-144; 1994.