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ISABEL LÓPEZ DE SILANES Y MANEL ESTELLER AN. R. ACAD. NAC. FARM.

immunodeficiency syndrome. Many evidences supports the impact
of ARE sequences on the posttranscriptional regulation of TNF-a
biosynthesis. Macrophages from mice with a genomic deletion of
the TNF-a ARE exhibit spontaneous production of TNF-a and their
TNF-a mRNA has a substantially prolonged half-life. Remarkably,
they also spontaneously develop a chronic inflammatory arthritis
and Crohn’s disease-like intestinal inflammation. In these studies, it
was shown that the absence of ARE-dependent translational control
of TNF mRNA was associated with the inability of p38/SAPK and
JNK/SAPK signalling pathways to regulate its translational
activation. The binding of a number of AUBPs to the ARE sequences
are directly responsible of the destabilization of the TNF-a mRNA.
TIA-1 and TTP are AUBPs that prevent the pathological expression
of tumor necroris factor alpha, TIA inhibiting its translation and
TTP promoting the degradation of TNF-a transcripts and, in turn,
functioning as arthritis suppressor genes (23). Therapies such as
neutralizing antibodies to TNF-a and chimeric soluble TNF-a
receptor have demonstrated efficacy against some of these conditions
in clinical trials. Furthermore, the TNF-a ARE is also known to
be a target for the mRNA stabilizing factor HuR, and mutations
of this cis-element both impair HuR binding and decrease TNF-a
protein production. Post-transcriptional mechanisms also regulate
the production of other proteins involved in inflammatory responses
such as cyclooxygenase-2 (COX-2) and matrixmetalloproteinase-13
(MMP-13). Pharmacologic inhibitors of COX-2 are potent, anti-
inflammatory agents, which significantly reduce the severity of
inflammatory arthritis.

Polymorphisms in the 3’UTR of multiple immune related mRNAs
are also associated with the development of human autoimmune
disease. For instance, deficient TCR ? chain on the T cells of patients
with systemic lupus erythematosus appears to be due to an
alternatively spliced form of the ? chain mRNA that has reduced
stability. As a consequence, these cells display abnormal TCR-
induced early signaling and have diminished IL-2 production (3).

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