Apoptotic effects of LPS on fibroblasts are indirectly mediated through TNFR1.
During periods of periodontal attachment loss, one of the most significant cellular changes is a decrease in the number of fibroblasts. We previously demonstrated that LPS induces apoptosis of fibroblastic cells in vivo, largely through TNF-alpha. We conducted in vivo experiments by subcutaneous inoculation of LPS in wild-type, TNFR1-/-R2-/-, TNFR1-/-, and TNFR2-/- mice to identify which TNF receptors are involved and the specific caspase pathway activated. LPS stimulated apoptosis through TNFR1 but not TNFR2, which was accompanied by the induced expression of 12 apoptotic genes. Fluorometric studies demonstrated that LPS in vivo significantly increased caspase-8 and caspase-3 activity, which was also dependent on TNF receptor signaling. By the use of specific caspase inhibitors, caspases-3 and -8 were shown to play an important role in LPS-induced apoptosis in vivo. Thus, LPS acts through TNFR1 to modulate the expression of apoptotic genes and activate caspases-3 and -8.
Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, MA 02118, USA.
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D000818:Animals; D015703:Antigens, CD / Q000187:drug effects* / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors / Q000187:drug effects; D004926:Escherichia coli; D005347:Fibroblasts / Q000187:drug effects*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects* / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D015398:Signal Transduction / Q000187:drug effects
D015703:Antigens, CD; D061945:Caspase Inhibitors; D004792:Enzyme Precursors; D008070:Lipopolysaccharides; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases