Abstract
Inflammation is a multifaceted process: beneficial as a defense mechanism but also detrimental depending on its severity and duration. At the site of injury, inflammatory cells are activated by a cascade of mediators, one of which is LITAF, a transcription regulator known to upregulate TNF-α. We previously showed that human LITAF forms a complex with human STAT6B, which translocates into the nucleus to upregulate cytokine transcription. To dissect the molecular implications of this complex, a murine model was developed and interactions between mouse STAT6B (mSTAT6B) and mouse LITAF (mLITAF) were analyzed. Both mLITAF and mSTAT6B expression were MyD88- and TLR ligand-dependent. Furthermore, mLITAF was found to mediate LPS-induced CCL2 gene transcription with the cooperation of mSTAT6B leading to CCL2 protein expression. In LITAF-deficient mice, mLITAF-mediated CCL2 production in macrophages was significantly reduced compared to the wild-type control animals. Mice knockdown for mSTAT6B by 6BsiRNA1 tail vein injection resulted in a decrease in serum TNF-α and CCL2 production. mLITAF/mSTAT6B complex is proposed to play a role in LPS-induced CCL2 expression and possibly other cytokines.
Highlights
The inflammatory response is the body’s defense mechanism against harmful stimuli or damage
In TLR-42/2 macrophages, mouse STAT6B (mSTAT6B) and mouse LPS-Induced TNF-Alpha Factor (LITAF) (mLITAF) were induced by P. gingivalis LPS (TLR-2 ligand) (No 5) but not by E. coli LPS (TLR-4 ligand) (No 6), while in TLR-22/2 macrophages, mSTAT6B and mLITAF were induced by E. coli LPS (No 8) but not by P. gingivalis LPS (No 7) compared to control
These findings indicate that mLITAF and mSTAT6B induction occurred with either TLR-2 or TLR-4 engagement
Summary
The inflammatory response is the body’s defense mechanism against harmful stimuli or damage. CCL2, known as monocyte chemoattractant protein-1 (MCP-1), is a chemokine associated with cerebral ischemia and rheumatoid arthritis [1], insulin resistance [11] and prostate cancer [2]. It is known that transcription factors must translocate into the nucleus using a nuclear core complex (NPC) to achieve gene transcription. We previously cloned and characterized a transcription factor that we named LPS-Induced TNF-Alpha Factor (LITAF) [12]. The cytoplasm-nucleus shuttling of LITAF sequentially enhances the transcription of the tumor necrosis factor-alpha (TNF-a) [13]. Proteins like LITAF contain a nuclear localization signal(s) (NLS) that facilitates translocation into the nucleus [14]
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