LPS‐INDUCED STAT3 AND CYTOKINE PROTEIN IN MOUSE BRAIN

Abstract

The peripheral immune system and the brain communicate through signaling mechanisms. Immune activation alters central nervous system (CNS) and the CNS modulates immune function. During infection there are changes in complex behavior, including sleep. What is not well known is by what mechanisms, and where, in brain immune signals act to alter sleep. Cytokines, such as IL‐1, TNF and IL‐6 mediate infection‐induced alterations in sleep. Receptor signaling for these cytokines include Signal Transducer and Activator of Transcription 3 (STAT3). To determine a potential role in altered sleep during immune challenge, we injected LPS into several mouse strains and determined changes in STAT3 and cytokine in discrete brain regions.Adult male mice (C57BL/6J; Balb/c; TLR4 mutant; n = 3‐4 / strain / condition) were injected IP at light onset with either 0.2ml vehicle or 10μg LPS (E. coli serotype O111:B4). These animals were sacrificed 2‐ or 4 h post injection. STAT3 from 2 h treatments and cytokine from 4 h treatments were analyzed in brain and spleen using Bioplex assays.STAT3 protein increased from 4 ‐ 10 fold 2 h after LPS in all samples assayed from C57BL/6J mice and Balb/c mice. In these two mouse strains, IL‐1, TNF and IL‐6 increased from 2.5 ‐ 11 fold 4 h after LPS. In contrast, due to the defect in TLR4 a signaling transducer for LPS, there were no LPS‐induced increases in STAT3 or in cytokine protein in the TLR4 mutant mice.These results demonstrate that the STAT3 signaling pathway for proinflammatory cytokines may be activated in discrete mouse brain regions and suggests that these pathways play a role in transducing peripheral immune signals into alterations in CNS‐regulated sleep/behavior.