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

Abstract

The effects of the carbocyclic nucleoside MDL 201,112 and the purine nucleoside adenosine on the interferon-gamma (IFN-gamma)-induced priming of macrophages (m phi s) for the respiratory burst and major histocompatibility class II (MHC class II) Ia+ antigen expression were compared. Priming of purified, peritoneal m phi s from Lewis (LEW/N) rats for 18 h with recombinant rat IFN-gamma (rRaIFN-gamma) in the presence of either adenosine (100 microM) or MDL 201,112 (10 microM) resulted in a fourfold decrease in superoxide anion (O2-) production after stimulation with opsonized zymosan. Both agents were effective even when added 2 or 4 h after rRaIFN-gamma treatment. Peritoneal m phi s from LEW/N rats stimulated with LPS/rRaIFN-gamma were observed to secrete immunoreactive and bioactive TNF-alpha 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 adenosine deaminase, or treatment with the nucleoside transport inhibitor dipyridamole, reversed the effects of adenosine; however, these agents at physiological concentrations had little or no effect on the inhibition of O2- release mediated by MDL 201,112. Furthermore, incubation of LEW/N m phi s for 18 h in vitro with rRaIFN-gamma 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 microM) or adenosine (100 microM). MDL 201,112 and adenosine were also effective in decreasing m phi opsonized zymosan-stimulated O2- levels and MHC class II Ia+ antigen expression in vivo. The effects of MDL 201,112 on the down-regulation of heat-killed M. tuberculosis-activated LEW/N m phi MHC class II Ia+ antigen expression in vitro appear to be mediated 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 summary, our data provide compelling evidence that immunoregulatory carbocyclic nucleoside analogues such as MDL 201,112 or adenosine appear to regulate LEW/N rat m phi activation through novel molecular mechanisms and may have important therapeutic implications for acute and chronic inflammatory diseases.

Shaping of monocyte and macrophage function by adenosine receptors

“…In agreement with the pharmacological data that IB-MECA was more potent than CGS 21680, an agonist which elicits its cellular effects mainly by activating the cAMP-PKA pathway (Lupica et al, 1990), the cAMP-dependent protein kinase inhibitor KT5720 failed to reverse the inhibitory effect of adenosine on fMLP-induced monocyte respiratory burst (Broussas et al, 1999). The inhibitory effect of adenosine on human monocyte/macrophage respiratory burst was recapitulated using both mouse (Si et al, 1997) and rat (Edwards et al, 1994) peritoneal macrophages; however, there was no detailed analysis of the adenosine receptors involved in either study.…”

Acute adenosinergic cardioprotection in ischemic-reperfused hearts

“…It has emerged that monocytes/macrophages are key cellular targets for adenosinergic regulation of inflammation, together with leukocytes and endothelium (30, 32, 100,147,174,191,203,212,216,262). Adenosine receptor stimulation in lipopolysaccharide (LPS)-stimulated monocytes/macrophages reduces production of tumor necrosis factor-␣ (TNF-␣) (30, 203, 245), interleukin-12 (101), and macrophage inflammatory protein (MIP)-1a (270), limits induction of inducible NO synthase (iNOS) (300), and represses expression of the membrane protein major histocompatibility complex II (71,300). Adenosine also inhibits endothelial cytokine secretion and expression of adhesion molecules (30) and NF-b activation and signaling stimulated by TNF-␣ in myeloid, lymphocytic, and epithelial cells (191).…”

Reversal of the antiinflammatory effects of methotrexate by the nonselective adenosine receptor antagonists theophylline and caffeine: Evidence that the antiinflammatory effects of methotrexate are mediated via multiple adenosine receptors in rat adjuvant arthritis

“…Several groups have reported that adenosine A 3 receptors, when occupied, diminish synthesis and release of cytokines, such as tumor necrosis factor ␣, that are thought to play a central role in the pathogenesis of RA (13)(14)(15)(16)39). Because A 3 receptors in rodents are insensitive to theophylline (17), our results are most consistent with the surprising finding that blockade of A 3 adenosine receptors does not contribute to the antiinflammatory effects of MTX in this model of arthritis.…”

“…Pharmacologic studies with the murine air pouch model of acute inflammatory disease demonstrate that MTX-mediated increases in exudate adenosine inhibit inflammation via interaction with an A 2 (probably A 2A ) receptor. Other pharmacologic studies have indicated that adenosine may also act at A 1 or A 3 receptors to inhibit inflammation (12)(13)(14)(15)(16).…”