Effects of phosphodiesterase inhibitors on cytokine production by microglia

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Abstract
Type III and IV phosphodiesterase inhibitors (PDEIs) have recently been shown to suppress the production of TNF-α in several types of cells. In the present study, we have shown that all the types of PDEIs, from type 1- to V-specific and non-specific, suppress the production of TNF-α by mouse microglia stimulated with lipopolysaccharide (LPS) in a dose-dependent manner. Certain combinations of three different types of PDEIs synergistically suppressed TNF-α production by microglia at a very low concentration (1 μM). Since some PDEIs reportedly pass through the blood-brain barrier (BBB), the combination of three PDEIs may be worth trying in neurological diseases, such as multiple sclerosis and HIV-related neurological diseases in which TNF-α may play a critical role. Some PDEIs also suppressed interleukin-1 (IL-1) and IL-6 production by mouse microglia stimulated with LPS. In contrast, the production of IL-10, which is known to be an inhibitory cytokine, was upregulated by certain PDEIs. The suppression of TNF-α and induction of IL-10 were confirmed at the mRNA level by RT - PCR. PDEIs may be useful anti-inflammatory agents by downregulating inflammatory cytokines and upregulating inhibitory cytokines in the central nervous system. (CNS).