Mechanism of negative regulation of rat glutathione S-transferase A2 by the cytokine interleukin 6.

A decrease in concentration of some liver proteins, including the detoxification enzyme glutathione S-transferase A2 (rGSTA2), occurs during the acute-phase response. Interleukin 6 (IL-6) with dexamethasone (DEX) decreases transcription of rGSTA2 in rat hepatocytes. The promoter region that mediates suppression of rGSTA2 was localized to 150 bp. These 150 bp were divided and used for electrophoretic mobility-shift assays. Induction of a protein that specifically bound to an oligonucleotide from this region required new protein synthesis and IL-6 with DEX in the culture media. The protein bound to part of the hepatocyte nuclear factor 1 (HNF1) site but was different from and did not displace HNF1. A core sequence, TGATT, was required for binding. The protein also bound to an HNF1 site in the albumin promoter. We hypothesize that IL-6 along with DEX induced a novel protein that decreased transcription of rGSTA2 and possibly albumin by interfering with the transactivating function of HNF1. The protein may be an important negative regulator of transcription during the acute-phase response.