TIA-1 is a translational silencer that selectively regulates the expression of TNF-alpha

TIA-1 and TIAR are related proteins that bind to an AU-rich element (ARE) i n the 3' untranslated region of tumor necrosis factor alpha (TNF-alpha) tra nscripts. To determine the functional significance of this interaction, we used homologous recombination to produce mutant mice lacking TIA-1. Althoug h lipopolysaccharide (LPS)-stimulated macrophages derived from wild-type an d TIA-1(-/-) mice express similar amounts of TNF-alpha transcripts, macroph ages lacking TIA-1 produce significantly more TNF-alpha protein than wild-t ype controls. The half-life of TNF-alpha transcripts is similar in wild-typ e and TIA-1-/- macrophages, indicating that TIA-1 does not regulate transcr ipt stability. Rather, the absence of TIA-1 significantly increases the pro portion of TNF-alpha transcripts that associate with polysomes, suggesting that TIA-1 normally functions as a translational silencer. TIA-1 does not a ppear to regulate the production of interleukin 1 beta, granulocyte-macroph age colony-stimulating factor or interferon gamma, indicating that its effe cts are, at least partially, transcript specific. Mice lacking TIA-1 are hy persensitive to the toxic effects of LPS, indicating that this translationa l control pathway may regulate the organismal response to microbial stress.