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.septic shock | multiplex

Dysregulated Inflammatory Signaling upon Charcot-Marie-Tooth Type 1C Mutation of SIMPLE Protein

“…4A) (34,37). Lastly, SIMPLE is also known as LITAF, which is induced upon inflammation and modulates cytokine gene induction (54)(55)(56). Together, these observations strongly suggested that SIMPLE might play a role in ubiquitin-mediated inflammatory signaling.…”

“…In addition, Tom1, which interacts with SIMPLE and was proposed as an ancestral type ESCRT-0 (91,92), facilitates the internalization and termination of the activated TLR complex and the TNF-␣ receptor (93). Furthermore, previous reports showed that SIMPLE-null mice are less sensitive to challenge by a lethal dose of LPS, in part due to altered cytokine levels (54,56,94). Thus, we expect a similar role for SIMPLE in the TLR complex and the TNF-␣ receptor signaling pathway.…”

“…Previous reports showed that SIMPLE plays a key role in cytokine production upon lipopolysaccharide (LPS) challenge (54,56). Increased tumor susceptibility upon CMT1C mutation of SIMPLE suggested that the levels of cytokine and chemokines might be altered.…”

Kavain inhibition of LPS-induced TNF-α via ERK/LITAF

“…E. coli LPS (100μg/mouse) every three days; and 3. Kavain (1~1.2mg/ mouse) every other day [10, 27] in a 10-day experimental protocol. Arthritis was monitored using a clinical score and later by histological analysis of hind dorsal paws.…”

“…The effects of E. coli LPS on transcription factor activity and expression have been widely investigated [10]. We cloned E. coli LPS Induced TNF-Alpha Factor (LITAF) [11], and showed that it partially controls TNF-α gene expression [12, 13].…”