title: Tumor necrosis factor-alpha mediates lipopolysaccharide-induced macrophage inflammatory protein-2 release from alveolar epithelial cells. Autoregulation in host defense.
abstract: Our recent studies have demonstrated that in response to lipopolysaccharide (LPS) challenge, alveolar epithelial cells produced tumor necrosis factor (TNF)-alpha, an early response cytokine in the inflammatory process. To investigate whether LPS-induced TNF-alpha release is related to other inflammatory mediators from the same cell type, we examined effects of LPS stimulation on macrophage inflammatory protein (MIP)-2 production by alveolar epithelial cells, and then examined the relationship between TNF-alpha and MIP-2 production. LPS stimulation induced a dose- and time-dependent release of MIP-2. The steady-state messenger RNA level of MIP-2 was significantly increased, with the MIP-2 protein localized within alveolar epithelial cells, as determined by confocal microscopy. The LPS-induced MIP-2 production is regulated at both the transcriptional and post-transcriptional levels. TNF-alpha also induced MIP-2 production from alveolar epithelial cells. Preincubation with an antisense oligonucleotide against TNF-alpha inhibited LPS-induced TNF-alpha in a dose-dependent and sequence-specific manner. The same antisense also inhibited MIP-2 production. The inhibitory effects were highly correlated. Polyclonal and monoclonal antibodies against TNF-alpha also attenuated LPS-induced MIP-2. These results suggest that LPS-induced MIP-2 release from alveolar epithelial cells may be mediated in part by TNF-alpha from the same cell type. This autoregulatory mechanism may amplify LPS-induced signals involved in host defense as well as in acute inflammatory reactions.
authors.affiliation: Thoracic Surgery Research Laboratory, Toronto Hospital, ON, Canada.
authors.forename: A M
authors.initials: AM
authors.lastname: Xavier
authors.forename: N
authors.initials: N
authors.lastname: Isowa
authors.forename: L
authors.initials: L
authors.lastname: Cai
authors.forename: E
authors.initials: E
authors.lastname: Dziak
authors.forename: M
authors.initials: M
authors.lastname: Opas
authors.forename: D I
authors.initials: DI
authors.lastname: McRitchie
authors.forename: A S
authors.initials: AS
authors.lastname: Slutsky
authors.forename: S H
authors.initials: SH
authors.lastname: Keshavjee
authors.forename: M
authors.initials: M
authors.lastname: Liu
mesh_terms: D000818:Animals; D001483:Base Sequence; D054426:Chemokine CXCL2; D018925:Chemokines / Q000096:biosynthesis; D017931:DNA Primers / Q000235:genetics; D004847:Epithelial Cells / Q000502:physiology; D006706:Homeostasis; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D015846:Monokines / Q000235:genetics / Q000378:metabolism*; D009500:Neutralization Tests; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000166:cytology / Q000502:physiology*; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
chemical_list: D054426:Chemokine CXCL2; D018925:Chemokines; D017931:DNA Primers; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D015846:Monokines; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha