LPS-Induced TNF-Alpha Factor (LITAF) is a transcriptional target of p53 – New evidences for a role of p53 in inflammatory diseases.

Salomon Amar, PhD and Anne-Laure Bolcato-Bellemin, PhD.

Boston University Medical Center, Boston MA, USA

Background : Lipolysaccharide (LPS) from the gram-negative bacterial outer membrane is probably the most potent stimulator of monocytes and macrophages for the synthesis of inflammatory mediators including tumor necrosis factor-alpha (TNF-a). TNF-a is a pleiotropic cytokine with action that can be either beneficial or detrimental to the host. The novel transcription factor LITAF (LPS-Induced TNF-Alpha Factor) plays an important role in regulating TNF-gene-expression. A LITAF-dependent functional element has been identified within the human TNF promoter, such that blocking LITAF synthesis in macrophages results in suppression of LPS-induced TNF gene expression. Polyak et al. (1997), have found an expressed sequence tag with 98% homology with LITAF, whose transcripts are induced by the p53 gene. The transcription factor p53 is probably the most important human tumor suppressor known and identification of its target genes should lead to a better understanding of its functions. Methods: In order to determine whether LITAF functions as a potential target of p53, its expression in p53 negative cells (MDAH041) was assessed by northern blot before and after LPS stimulation. The effect of the inhibition of p53 in fibroblastic cells, on the expression of various cytokines, including TNFb, Ltb, TNFa, IFNg, IFNb, TGFb3, TGFb2, and TGFb1 was also demonstrated by RNase protection assay. Results: In the absence of p53 expression, LITAF-transcripts are not expressed. Moreover an inhibition of p53 and then LITAF expression leads to an inhibition of the cytokine TGFb1 after LPS exposure, the other cytokines were either not expressed in the cell type studied or their expression not modified. Conclusion: Our results demonstrate that the transcription factor LITAF is a target gene for p53. This finding makes a unique direct connection between LPS stimulation and the activation of LITAF in inflammatory diseases and implies a potential important role of p53 in the regulation of inflammation.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Molecular Pathology.