Effects of phosphodiesterase inhibitors on cytokine production by microglia

Abstract

Type III and IV phosphodiesterase inhibitors (PDEIs) have recently been shown to suppress the production of TNF-alpha in several types of cells. In the present study, we have shown that all the types of PDEIs, from type I- to V-specific and non-specific, suppress the production of TNF-alpha by mouse microglia stimulated with lipopolysaccharide (LPS) in a dose-dependent manner. Certain combinations of three different types of PDEIs synergistically suppressed TNF-alpha production by microglia at a very low concentration (1 microM). 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-alpha may play a critical role. Some PDEIs also suppressed interleukin-I (IL-I) 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-alpha 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).

Inhibition of phosphodiesterase 4 reduces ethanol intake and preference in C57BL/6J mice

“…Indeed, rolipram dose-dependently reduced LPS-induced production of TNFα in rat brain and microglia (Buttini et al, 1997; Yoshikawa et al, 1999). Furthermore, LPS, pro-inflammatory cytokines, and ethanol all increased the activity of PDE4 in several types of cells (microglia, astrocytes, bronchial epithelial), and these effects were reversed by rolipram (Buttini et al, 1997; Forget et al, 2003; Ghosh et al, 2012).…”

Cilostazol Decreases Ethanol-Mediated TNFalpha Expression in RAW264.7 Murine Macrophage and in Liver from Binge Drinking Mice

“…Among the regulators of TNFα expression, it has been clearly demonstrated that the elevation of cyclic AMP (cAMP) suppresses the expression of TNFα in macrophage [8,9]. In consistent with these observations, phosphodiesterase (PDE) inhibitors suppressed TNFα production in macrophage through elevating intracellular cAMP [10-12]. …”

The Effect of Pulse Methylprednisolone Plus Theophylline Treatment on Clinical, Pulmonary and Inflammatory Markers in Relapses of Multiple Sclerosis

“…Phosphodiesterase inhibitors (PDEI) suppress the catabolism of cAMP and cGMP, thereby they increase intracellular levels of these cyclic nucleotides and modulate the cytokine secretion (7)(8)(9). Previous studies have shown that production of Thi cytokines especially TNF-alpha might be suppressed by PDEI (10)(11)(12)(13).…”