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

Andrzej P Herman,Joanna Bochenek,Anna Herman,Hanna Antushevich,Dorota Tomaszewska-Zaremba,Agata Krawczyńska

doi:10.1155/2014/475152

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.

Highlights

Hypothalamus is the brain region responsible for integration and processing of signals from endocrine, nervous, and immune systems
Our study demonstrated that prolonged inflammation induced through 7 days of LPS treatment elevated local synthesis of IL-1β, IL-6, and TNFα in the hypothalamus of sheep
These results fully support the data obtained in previous studies with single and repeated LPS injections which reported the potentiation of proinflammatory cytokines synthesis in the brain of mice [6, 31]

Summary

Introduction

Hypothalamus is the brain region responsible for integration and processing of signals from endocrine, nervous, and immune systems. During the development of inflammatory response, the increased concentration of proinflammatory cytokines is observed both in the cerebrospinal fluid and in brain parenchyma [6, 8, 9]. The origin of these proinflammatory cytokines in central nervous system seems to be differentiated: the peripheral cytokines can cross the blood-brain barrier through fenestrated brain capillaries in the choroid plexus, organum vasculosum of the lamina terminalis, median eminence, subfornical organ, and area postrema [10]. The cytokines may be transported into the brain via blood-brain barrier by saturated, self-inhibitable

Methods

Results

Conclusion