title: Whole-body deletion of LPS-induced TNF-α factor (LITAF) markedly improves experimental endotoxic shock and inflammatory arthritis.
abstract: LPS-induced TNF-α factor (LITAF) mediates cytokine expression in response to endotoxin challenge. Previously, we reported that macrophage-specific LITAF-deficient (macLITAF-/-) mice exposed to LPS have a delayed onset in the serum levels of proinflammatory cytokines and prolonged persistence of anti-inflammatory cytokines, but only partial protection from endotoxic shock. We postulated that greater protection might be achieved if LITAF were deleted from all LITAF-producing cells, including macrophages. Using a Cre-loxP system, we engineered a tamoxifen-induced recombination mouse [tamLITAF(i)-/-] that resulted in whole-body LITAF deficiency. Our findings demonstrate that (i) tamLITAF(i)-/- mice are more resistant to systemic Escherichia coli LPS-induced lethality than our previous macLITAF-/- mice, providing evidence that LITAF-producing cells other than LysMCre-positive cells play an important role in mediating endotoxic shock; (ii) tamLITAF(i)-/- mice show a similar pattern of cytokine expression with decreased proinflammatory and prolonged anti-inflammatory mediators compared with WT mice; and (iii) tamLITAF(i)-/- mice, compared with WT mice, display a significant reduction in bone resorption and inflammation associated with a local chronic inflammatory disease--namely, collagen antibody-induced arthritis. Our findings offer a unique model to study the role of LITAF in systemic and chronic local inflammatory processes, and pave the way for anti-LITAF therapeutic approaches for the treatment of TNF-mediated inflammatory diseases.
authors.affiliation: Center for Anti-Inflammatory Therapeutics, Department of Periodontology and Oral Biology, Boston University Goldman School of Dental Medicine, Boston, MA 02118, USA.
authors.forename: Jamie C
authors.initials: JC
authors.lastname: Merrill
authors.forename: Jian
authors.initials: J
authors.lastname: You
authors.forename: Cara
authors.initials: C
authors.lastname: Constable
authors.forename: Susan E
authors.initials: SE
authors.lastname: Leeman
authors.forename: Salomon
authors.initials: S
authors.lastname: Amar
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D015153:Blotting, Western; D003433:Crosses, Genetic; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins; D004926:Escherichia coli; D005786:Gene Expression Regulation / Q000276:immunology*; D005818:Genetic Engineering / Q000379:methods; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics; D016133:Polymerase Chain Reaction; D011995:Recombination, Genetic / Q000187:drug effects; D012772:Shock, Septic / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D013629:Tamoxifen / Q000494:pharmacology; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics
chemical_list: D016207:Cytokines; D017931:DNA Primers; D004268:DNA-Binding Proteins; D008070:Lipopolysaccharides; C492727:Litaf protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; D013629:Tamoxifen