The molecular regulatory effect of intracerebroventricular thymulin on endotoxin-mediated NF-kB nuclear translocation and activation in vivo

Abstract

The nuclear factor-kB (NF-kB) is one member of a ubiquitously expressed family of Rel-related transcription factors that serve as critical regulators of proinflammatory genes. The immunomodulatory potential of thymulin and its effect on NF-kB in vivo, particularly in the central nervous system (CNS), is not well characterized. In this study, the role of endotoxin (ET) in regulating NF-kB was unraveled in various compartments of the CNS. Stereotaxic localization reverberated specific intracerebroventricular (ICV) injection of ET into the CNS, with or without pretreatment with ICV thymulin. Treatment with ET upregulated the expression and nuclear trans-localization of NF-kB1 (p50), NF-kB2 (p52), RelA (p65), RelB (p68) and c-Rel (p75) in the hippocampus (HC), an effect abrogated by ICV pretreatment with thymulin. Thymulin modulated the phosphorylation of IkB-a in the HC by upregulating the cytosolic accumulation of IkB-a and downregulating its phosphorylation (pIkB-a). Further analysis of the DNA-binding activity revealed an upregulated activity in the HC relative to saline-constitutive expression of the RelA (p65) subunit. ET did not induce the DNA-binding activity of NF-kB in the diencephalon (DE) or substantia nigra (SN) at various time points, when compared with baseline levels of expression. Intraperitoneal (IP) injections of ET in vivo upregulated the expression of NF-kB subunits in the liver and reduced the cytosolic accumulation of IkB-a by inducing pIkB-a. Furthermore, IP pretreatment with thymulin followed by ICV inje