Peripheral injection of SB203580 inhibits the inflammatory-dependent synthesis of proinflammatory cytokines in the hypothalamus

Abstract

The study was designed to determine the effects of peripheral injection of SB203580 on the synthesis of interleukin- (IL-) 1β, IL-6, and tumor necrosis factor (TNF) α in the hypothalamus of ewes during prolonged inflammation. Inflammation was induced by the administration of lipopolysaccharide (LPS) (400 ng/kg) over 7 days. SB203580 is a selective ATP-competitive inhibitor of the p38 mitogen-activated protein kinase (MAPK), which is involved in the regulation of proinflammatory cytokines IL-1β, IL-6 and TNFα synthesis. Intravenous injection of SB203580 successfully inhibited (P < 0.01) synthesis of IL-1β and reduced (P < 0.01) the production of IL-6 in the hypothalamus. The p38 MAPK inhibitor decreased (P < 0.01) gene expression of TNFα but its effect was not observed at the level of TNFα protein synthesis. SB203580 also reduced (P < 0.01) LPS-stimulated IL-1 receptor type 1 gene expression. The conclusion that inhibition of p38 MAPK blocks LPS-induced proinflammatory cytokine synthesis seems to initiate new perspectives in the treatment of chronic inflammatory diseases also within the central nervous system. However, potential proinflammatory effects of SB203580 treatment suggest that all therapies using p38 MAPK inhibitors should be introduced very carefully with analysis of all expected and unexpected consequences of treatment.

Figure 1

Effect of lipopolysaccharide (LPS) (400 ng/kg; i.v./7 days) and SB203580 (500 μg/kg) injections on IL-1β (a), IL-6 (b), and TNFα (c) expression in the hypothalamus on day 7 of the experiment. a, b, c—P < 0.01 (indicate values that differ significantly from the control, SB203580 control, and LPS treated groups, resp., according to the Mann-Whitney U test). Data are presented as a mean value ± S.E.M.

Figure 2

Influence of lipopolysaccharide (LPS) (400 ng/kg; i.v./7 days) and SB203580 (500 μg/kg) injections on the gene expression of IL-1β (a) and IL-1R1 (b) in the hypothalamus on day 7 of the experiment. a, b, c—P < 0.01 (indicate values that differ significantly from the control, SB203580 control, and LPS treated groups, resp., according to the Mann-Whitney U test). Data are presented as a mean value ± S.E.M.

Figure 3

Effect of lipopolysaccharide (LPS) (400 ng/kg; i.v./7 days) and SB203580 (500 μg/kg) injections on the gene expression of IL-6 (a) and IL-6R (b) in the hypothalamus on day 7 of the experiment. a, b, c—P < 0.01 (indicate values that differ significantly from the control, SB203580 control, and LPS treated groups, resp., according to the Mann-Whitney U test). Data are presented as a mean value ± S.E.M.

Figure 4

Effect of lipopolysaccharide (LPS) (400 ng/kg; i.v./7 days) and SB203580 (500 μg/kg) injections on the gene expression of TNFα (a), TNFR1 (b), and TNFR2 (c) in the hypothalamus on day 7 of the experiment. a, b, c—P < 0.01 (indicate values that differ significantly from the control, SB203580 control, and LPS treated groups, resp., according to the Mann-Whitney U test). Data are presented as a mean value ± S.E.M.