Zaprinast, an inhibitor of cGMP‐selective phosphodiesterases, enhances the secretion of TNF‐α and IL‐1β and the expression of iNOS and MHC class II molecules in rat microglial cells

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Abstract
Proinflammatory cytokines produced by activated glial cells may in turn augment the immune/inflammatory reactions of glial cells through autocrine and paracrine routes. The NO/cGMP signaling represents one of the reactions of activated glial cells. We investigated whether the production of proinflammatory cytokines by glial cells is affected by NO‐dependent downstream cGMP signaling. In primary cultures of mixed astrocytes and microglial cells, zaprinast (0.1 mM), an inhibitor of cGMP‐selective phosphodiesterases, enhanced the basal and LPS (1.0 μg/ml)‐induced secretion of TNF‐α and IL‐1β. Zaprinast also enhanced NO production induced by LPS or IFN‐γ (100 U/ml), and in microglial cell cultures, but not in astrocyte cultures, zaprinast enhanced the basal and the IFN‐γ‐induced production of the cytokines, TNF‐α and IL‐1β, and of NO. This upregulation by zaprinast was partially inhibited by KT5823 (1.0 μM), an inhibitor of protein kinase G. The LPS‐induced production of TNF‐α, IL‐1β, and NO was inhibited by ODQ (50 μM), an inhibitor of soluble guanylyl cyclase, and by KT5823. Immunohistochemical analysis of mixed glial cell cultures showed that LPS/IFN‐γ‐induced iNOS expression and the enhanced expression of iNOS by zaprinast were restricted to microglial cells. Zaprinast enhanced the IFN‐γ (200 U/ml)‐induced expression of MHC Class II molecules in astrocytes and microglial cells in mixed cultures, but did not enhance this IFN‐γ‐induced expression in pure astrocytes, which lacked paracrine TNF‐α from microglial cells. Summarizing, zaprinast, which is associated with cGMP/protein kinase G signaling, may augment central immune/inflammatory reactions, possibly via the increased production of TNF‐α and IL‐1β by activated microglial cells.