Gene regulation of the serine proteinase inhibitors α1-antitrypsin and α1-antichymotrypsin

Abstract

The serine proteinase inhibitors (serpins) are a superfamily of proteins with a diverse set of functions, including the control of blood coagulation, complement activation, programmed cell death and development. The most abundant serpins in human plasma are α1-antitrypsin (AAT) and α1-antichymotrypsin (ACT). During inflammation, circulating levels can increase by up to 3-fold for the former and by 4–5-fold for the latter. The major site for increased synthesis is the liver. Other tissues, such as the lung, are also capable of synthesizing AAT and ACT, and expression can be increased by up to 100-fold by cytokines. There is a tissue-specific promoter for the liver, and alternative promoters for other tissues that express AAT. Basal AAT expression is regulated by the synergistic action of the tissue-specific transcription factors hepatocyte nuclear factors 1α and 4. An enhancer positioned approx. 1.2 kb from the end of the last exon in the 3′ flanking sequence modulates cytokine-induced expression by interleukin-6 and oncostatin M. Microcell hybrid transfection studies have shown that a sequence containing 15 kb of 5′ flanking sequence is sufficient to allow stable expression of AAT in a position-independent manner. There is probably a single promoter for ACT. Oncostatin M-inducible elements have been identified in the 5′ flanking sequence approx. 100 bp upstream from the transcription initiation site, and a further interleukin-1-responsive enhancer has been identified approx. 13 kb upstream. The pathways for a humoral response are being mapped at high resolution.