LITAF Mediation of Increased TNF-α Secretion from Inflamed Colonic Lamina Propria Macrophages

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.

Local injection of dsRNA targeting calcitonin receptor-like receptor (CLR) ameliorates Clostridium difficile toxin A-induced ileitis

“…Other experiments have shown that in diet-induced obesity, changes in macrophage function were revealed only after bacterial challenge (21). Lamina propria macrophages that were isolated from inflamed tissue had heightened TNF-α secretion, even without stimulation, suggesting that their environment altered their function (22). Thus, our finding that a role for CLR was only clearly demonstrated after inflammatory responses is paralleled by similar findings in other systems.…”

The natural compound celastrol inhibits necroptosis and alleviates ulcerative colitis in mice

“…Since TNF-α is mainly induced by the NF-κB, however celastrol is known to inhibit the NF-κB signal pathway [38]. Bushell et al [39] have discovered that TNF-α can be induced by the LPS-induced-TNF-α-Factor (LITAF) in inflamed colonic lamina propria macrophages, which is independent from NF-κB. We speculate that the invariant level of TNF-α between the saline group and the celastrol group may be produced via the LITAF signaling after the NF-κB inhibition based on the observation that no significant difference was found on the number of macrophages between the saline and celastrol groups.…”

Minocycline ameliorates LPS-induced inflammation in human monocytes by novel mechanisms including LOX-1, Nur77 and LITAF inhibition

“…Initially characterized as an LPS-dependent major TNF-α inducer, it was later reported that LITAF activation induces production not only of TNF-α but also of other inflammatory cytokines such as IL-1β and IL-6 [16], that LITAF is an important factor mediating macrophage activation during acute and chronic inflammation [15,31], and that its degree of activation determines sensitivity and resistance to LPS [16]. …”