Effects of phosphodiesterase inhibitors on cytokine production by microglia.
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).
Yoshikawa
M
M
Department of Neurology, Nara Medical University, Kashihara, Japan.
Suzumura
A
A
Tamaru
T
T
Takayanagi
T
T
Sawada
M
M
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000676:Amrinone / Q000494:pharmacology; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology; D000077407:Cilostazol; D005576:Colforsin / Q000494:pharmacology; D017931:DNA Primers; D004176:Dipyridamole / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000276:immunology; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects* / Q000201:enzymology* / Q000276:immunology; D009103:Multiple Sclerosis / Q000276:immunology*; D010208:Papaverine / Q000494:pharmacology; D010431:Pentoxifylline / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000276:immunology / Q000378:metabolism; D011719:Pyrazines; D011760:Pyrrolidinones / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020889:Rolipram; D013777:Tetrazoles / Q000494:pharmacology; D013806:Theophylline / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D014748:Vinca Alkaloids / Q000494:pharmacology*; D014970:Xanthines / Q000494:pharmacology
D000897:Anti-Ulcer Agents; D017931:DNA Primers; D007375:Interleukin-1; D015850:Interleukin-6; D010726:Phosphodiesterase Inhibitors; D011719:Pyrazines; D011760:Pyrrolidinones; D011804:Quinolines; D011994:Recombinant Proteins; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; D014748:Vinca Alkaloids; D014970:Xanthines; D005576:Colforsin; C013983:vinpocetine; C041667:vesnarinone; C032114:propentofylline; D004176:Dipyridamole; D013806:Theophylline; D010208:Papaverine; D010727:Phosphoric Diester Hydrolases; D000676:Amrinone; D020889:Rolipram; D000077407:Cilostazol; D010431:Pentoxifylline; D015056:1-Methyl-3-isobutylxanthine