Abstract
Dysregulation of TNF-α in lamina propria macrophages (LPM) is a feature of inflammatory bowel diseases (IBD). LPS-Induced-TNF-Alpha-Factor (LITAF) is a transcription factor that mediates TNF-α expression. To determine whether LITAF participates in the mediation of TNF-α expression in acutely inflamed colonic tissues, we first established the TNBS-induced colonic inflammation model in C57BL/6 mice. LPM were harvested from non-inflamed and inflamed colonic tissue and inflammatory parameters TNF-α and LITAF mRNA and protein levels were measured ex-vivo. LPM from TNBS-treated mice secreted significantly more TNF-α at basal state and in response to LPS than LPM from untreated mice (p<0.05). LITAF mRNA and protein levels were elevated in LPM from TNBS compared with untreated animals and LPS further increased LITAF protein levels in LPM from inflamed tissue (P<0.05). To further confirm the role of LITAF in acutely inflamed colonic tissues, TNBS-induced colonic inflammation was produced in LITAF macrophage specific knockout mice (LITAF mac -/- mice) and compared to wild type (WT) C57BL/6. Twenty four hours following TNBS administration, colonic tissue from LITAF mac -/- mice had less MPO activity and reduced colonic TNF-α mRNA then WT C57BL/6 mice (p<0.05). LPM harvested from LITAF mac -/- secreted significantly less TNF-α in response to LPS than wild type (WT) C57BL/6 (p<0.05). This study provides evidence that LITAF contributes to the regulation of TNF-α in LPM harvested following acute inflammation or LPS treatment paving the way for future work focusing on LITAF inhibitors in the treatment of TNF-α-mediated inflammatory conditions.
Highlights
Tumor Necrosis Factor alpha (TNF-a) is a cytokine that has a wide variety of functions including immune cell activation and proliferation.[1,2] TNF-a is produced primarily by macrophages in response to bacterial byproducts such as lipopolysaccharide (LPS)
The baseline secretion of TNF-a into the media was significantly increased in freshly harvested lamina propria macrophages (LPM) from inflamed colonic tissue from TNBS-treated mice compared to LPM from non-inflamed colonic tissue from non-treated controls (p,0.001) clearly documenting a change in the properties of the LPM in response to the inflammatory stimulus (Figure 2A)
These findings are further strengthened by our data demonstrating that TNF-a secretion is significantly reduced in LPM harvested from the inflamed colons of LITAF mac -/- knockout mice in which the LITAF gene has been selectively deleted from macrophages
Summary
Tumor Necrosis Factor alpha (TNF-a) is a cytokine that has a wide variety of functions including immune cell activation and proliferation.[1,2] TNF-a is produced primarily by macrophages in response to bacterial byproducts such as lipopolysaccharide (LPS). Inflammatory bowel diseases such as Crohn’s Disease (CD), are inflammatory disorders characterized by recurring episodes of acute colonic inflammation in the gastrointestinal tract.[3] Clinical and molecular studies have implicated TNF-a as a key mediator in gastrointestinal inflammatory diseases. Continued research into new strategies for the therapeutic regulation of TNF-a action is warranted
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