NYMC Faculty Publications

Whole-Body Deletion of LPS-Induced TNF-α Factor (LITAF) Markedly Improves Experimental Endotoxic Shock and Inflammatory Arthritis

Author Type(s)

Faculty

Additional Author Affiliation

Touro College of Dental Medicine at NYMC

DOI

10.1073/pnas.1111492108

Journal Title

Proceedings of the National Academy of Sciences of the United States of America

First Page

21247

Last Page

21252

Document Type

Article

Publication Date

12-27-2011

Department

Pharmacology

Keywords

Analysis of Variance, Animals, Arthritis, Experimental, Blotting, Western, Crosses, Genetic, Cytokines, DNA Primers, DNA-Binding Proteins, Escherichia coli, Gene Expression Regulation, Genetic Engineering, Immunohistochemistry, Immunotherapy, Lipopolysaccharides, Mice, Mice, Knockout, Nuclear Proteins, Polymerase Chain Reaction, Recombination, Genetic, Shock, Septic, Tamoxifen, Transcription Factors

Disciplines

Medicine and Health Sciences

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.

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