ag-490 and Encephalitis

The functional significance for activation of inflammatory transcription factors, such as signal transducer and activator of transcription (STAT3), nuclear factor (NF)κB or NF-interleukin (IL)6 and their contribution to the induction of brain controlled sickness responses, such as fever, during infection and inflammation is unknown. Using AG490, previously shown to inhibit the STAT3- and NF-IL6-signaling pathway, we therefore investigated the central involvement of these two signaling pathways in mediating sickness behavior, fever and accompanying brain inflammation induced by peripheral lipopolysaccharide (LPS)-stimulation. Rats pre-treated i.c.v. with AG490 1 h before the i.p. LPS-challenge (100 μg/kg) showed a modestly exaggerated fever, attenuated adipsia and almost unimpaired locomotor activity compared to LPS-controls receiving vehicle (i.c.v.). The LPS-induced anorexia was not altered and AG490 did not have any effect on rats receiving PBS (i.p.). We did observe effects of AG490 on STAT3-signaling at 4 h, while AG490-mediated changes in brain activity of inflammatory transcription factors at 8 h were not significant. Increased NF-IL6 and suppressor of cytokines 3 mRNA-expression in AG490/LPS-treated rats were indicative of a compensative activation at 24 h. Moreover, a significant decrease in hypothalamic anti-inflammatory IL-10-expression and an increase in inflammatory microsomal prostaglandin E synthase (mPGES) mRNA-expression 8 h after LPS-injection was revealed in AG490 pre-treated animals compared to solvent-treated LPS-controls. In summary, we have shown a dissociation between the effects of central AG490 treatment on fever and components of sickness behavior, which appears to be related to reduced IL-10 and increased mPGES-expression in the brain. Thus, AG490 might have therapeutic potential to reduce sickness behavior.

Topics: Animals; Behavior, Animal; Body Temperature Regulation; Brain; Disease Models, Animal; Encephalitis; Enzyme Inhibitors; Gene Expression Regulation; Inflammation Mediators; Injections, Intraventricular; Janus Kinases; Lipopolysaccharides; Male; Nerve Tissue Proteins; Neurons; Rats; Rats, Wistar; RNA, Messenger; STAT Transcription Factors; Tyrphostins

Microglia, the resident macrophage of the brain, mediates immune and inflammatory responses in the central nervous system (CNS). Activation of microglia and secretion of inflammatory cytokines associate with the pathogenesis of CNS diseases, including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease, prion disease, and AIDS dementia. Microbial pathogens, cytokines, chemokines, and costimulatory molecules are potent inducers of microglial activation in the CNS. Signaling through its receptor, IL-3 induces the activation of JAK-STAT and MAP kinase pathways in microglial cells. In this study, we found that in vitro treatment of EOC-20 microglial cells with tyrphostin AG490 blocked IL-3-induced tyrosine phosphorylation of JAK2, STAT5A, and STAT5B signaling proteins. Stable transfection of EOC-20 cells with a dominant negative JAK2 mutant also blocked IL-3-induced tyrosine phosphorylation of JAK2, STAT5A, and STAT5B in microglia. The blockade of JAK2-STAT5 pathway resulted in a decrease in IL-3-induced proliferation and expression of CD40 and major histocompatibility complex class II molecules in microglia. These findings highlight the fact that JAK2-STAT5 signaling pathway plays a critical role in mediating IL-3-induced activation of microglia.

Topics: Animals; CD40 Antigens; Cell Division; Cell Line; DNA-Binding Proteins; Encephalitis; Enzyme Inhibitors; Gliosis; Histocompatibility Antigens Class II; Humans; Interleukin-3; Janus Kinase 2; Mice; Microglia; Milk Proteins; Neurodegenerative Diseases; Phosphorylation; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Signal Transduction; STAT5 Transcription Factor; Trans-Activators; Transfection; Tumor Suppressor Proteins; Tyrphostins