The success of tumor necrosis factor (TNF) antagonists in the therapy of inflammatory arthritides has established the central role of this cytokine in the pathogenesis of these disorders. TNF is notable in that it is predominantly controlled at the post-transcriptional level in macrophages. TNF biosynthesis is highly regulated by the AU-rich element (AURE) found in its 3' untranslated region. This AURE regulates both the stability and rate of translation of TNF mRNA. In the macrophage, the ERK, JNK, and p38 SAPK signaling pathways converge on the AURE in regulating the nuclear export, stability and translation of TNF mRNA. Second, the C3H zinc finger protein, tristetraprolin (TTP), appears to play a major role in the post-transcriptional regulation of TNF by binding the AURE. Recent studies have identified that TTP is a target of the p38 SAPK/MAPKAP K2 kinase (MK2) pathway. Phosphorylation of TTP by MK2 has been reported in vitro and in vivo; data suggest that MK2 activation inactivates the function of TTP as a destabilizing protein.
Intriguingly, TTP binding to the AURE does not appear to be regulated by this phosphorylation. Rather, the function of TTP seems to be modulated through interactions with specific proteins that alter its subcellular localization. This creates a model where TTP provides specificity in binding cytokine-type AURE but the consequences of this interaction are determined by protein–protein interactions. Second, we have identified that TTP does not bind all AURE, but rather exhibits specificity for nUAUUUAUn sequences. Third, we have identified that TTP regulates its own mRNA stability. Fourth, we have demonstrated that TTP localizes to the polysomes in the context of macrophage activation by lipopolysaccharide. Fifth, we have demonstrated that TTP is expressed in many different hematopoietic cells and appears to function as an AURE binding protein. Thus, although the role of TTP in TNF biology is best understood in the macrophage, it appears that some, if not all, of these concepts may be relevant to other cells involved in the immune and inflammatory response.
Supported by funding from the Veteran's Administration and National Institutes of Health.