TRANSLATIONAL CONTROL OF THE ACUTE PHASE RESPONSE

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Inflammatory signals from macrophage derived cytokines such as Il-1beta, Il-6, and TNF reprogram liver gene transcription during the acute phase response (APR). However the translational efficiency of hepatic H- and L- ferritin mRNAs (H- and L-mRNAs) also increases in response to Il-1beta in the absence of changes in mRNA levels. This suggests that inflammatory cytokines may not only transduce signals which stimulate increased transcription of APR genes but also change gene expression by altering mRNA translation. Increased translation and accumulation of ferritin would increase the iron storage capacity of tissues, and remove iron from serum. This may afford a protective response during the APR. The transcription of typical human liver APR genes such as serum amyloid A (SAA) and alpha-1 acid glycoprotein (AGP) increases after exposure to inflammatory cytokines. However liver SAA and AGP gene expression is also controlled by post- transcriptional mechanisms after their appearance as stable mRNAs in the cytoplasm. These proteins are translated and exported as another part of an adaptive response to minimize damage during inflammation. The following experiments are planned: A)An examination of the role of Il-1beta, TNF, & Il-6 in H- & L- ferritin gene translation in hepatoma (HepG2 & Hep3B) and endothelial cells. B)An analysis of the mechanisms influencing translational control during the acute phase response. The RNA sequences in ferritin mRNAs which are translationally responsive to Il-1beta, TNF and Il-6 will be assessed. RNA elements in the 5' non coding regions of H- and L- mRNA exhibit sequence similarity with a motif in other APR gene 5' noncoding regions, including AGP. The hypothesis that translational regulation might act through such "RNA enhancers" will be tested. C)Poly(A) tails lengthen or shorten at the 3' of liver mRNAs during the APR. The effect of this on AGP, SAA, and ferritin translation and RNA stability will be characterized in hepatoma cells exposed to cytokines.