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Effects of phosphodiesterase inhibitors on cytokine production by microglia

Department of Neurology, Nara Medical University, Shijocho, Kashihara 634

Akio Suzumura

Department of Neurology, Nara Medical University, Shijocho, Kashihara 634

Tsukasa Tamaru

Department of Neurology, Nara Medical University, Shijocho, Kashihara 634

Tetsuya Takayanagi

Department of Neurology, Nara Medical University, Shijocho, Kashihara 634

Makato Sawada

Division of Pathology and Biochemistry, Institute for Comprehensive Medical Sciences, Fujita Health University, Toyoake, Aichi 470-11 Japan

Type III and IV phosphodiesterase inhibitors (PDEIs) have recently been shown to suppress the production of TNF- 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- by mouse microglia stimulated with lipopolysaccharide (LPS) in a dose-dependent manner. Certain combinations of three different types of PDEIs synergistically suppressed TNF- 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- 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- 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).

Key Words: multiple sclerosis • TNFa • phosphodiesterase inhibitor • microglia

Multiple Sclerosis, Vol. 5, No. 2, 126-133 (1999)
DOI: 10.1177/135245859900500210


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