title: Lipopolysaccharide differentially modulates expression of cytokines and cyclooxygenases in dorsal root ganglion cells via Toll-like receptor-4 dependent pathways.
abstract: We have examined the functional expression of Toll-like receptor 4 (TLR4) in adult male rat dorsal root ganglion (DRG) cells in culture by studying changes in pro-inflammatory cytokines and cyclooxygenase (COX)-dependent prostanoid production. In the mixed population of DRG neurons and glial cells, only DRG neurons expressed cell surface TLR4 along with MD-2 and CD14. This classical TLR4 signaling complex on DRG neurons responded to lipopolysaccharide (LPS) with a TLR4-dependent and time-dependent increase in interleukin-1β and tumor necrosis factor-α mRNA expression which was entirely dependent on NF-κB activity. In contrast, after 2-h incubation with DRG cells, LPS-stimulated COX-2 was regulated by both NF-κB and transactivation of epidermal growth factor receptor (EGFR) with potential downstream activation of ERK1/2 and p38 kinase. In contrast to this evidence for myeloid differentiation primary response gene-88 (MyD88)-dependent signaling, no evidence was obtained for TIR-domain-containing adaptor-inducing interferon-ß (TRIF)-dependent signaling from TLR4 in DRG neurons. LPS surprisingly produced a time-dependent decrease in COX-1 protein which likely facilitates the COX-2-dependent production of prostaglandin E2 and prostacyclin. Our study is the first to demonstrate the activation of TLR4-dependent production of prostaglandin E2 and prostacyclin in DRG cell cultures. Our findings support the concept that the activation of TLR4 on primary sensory neurons by endogenous ligands may underlie neuropathic and inflammatory pain states.
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region.
authors.forename: K-H
authors.initials: KH
authors.lastname: Tse
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region.
authors.forename: K B S
authors.initials: KB
authors.lastname: Chow
authors.affiliation: Faculty of Dentistry, The University of Hong Kong, Hong Kong Special Administrative Region.
authors.forename: W K
authors.initials: WK
authors.lastname: Leung
authors.affiliation: Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong Special Administrative Region.
authors.forename: Y H
authors.initials: YH
authors.lastname: Wong
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region. Electronic address: helenwise@cuhk.edu.hk.
authors.forename: H
authors.initials: H
authors.lastname: Wise
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000166:cytology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000187:drug effects*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism
chemical_list: D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D008070:Lipopolysaccharides; D012333:RNA, Messenger; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D014404:Tubulin; D011451:Prostaglandin-Endoperoxide Synthases
keywords: Toll-like receptor-4; cell signaling; dorsal root ganglia; lipopolysaccharide; neuroinflammation