Cytokine modulation of liver annexin 1 expression during experimental endotoxemia

Annexin 1 (ANXA1) is a calcium-binding protein endowed with anti-inflammato ry properties. Using an extra-hepatic system, we showed that interleukin (I L)-6 regulates ANXA1 expression at the transcriptional level. The purpose o f this study was to determine whether ANXA1 synthesis was modulated by IL-6 during experimental inflammation. We have compared liver ANXA1 expression during systemic and localized inflammatory reaction, using lipopolysacchari de (LPS) and turpentine. LPS treatment strongly induced ANXA1 expression in the liver of wild-type (WT) animals (+600%) whereas a modest increase (+60 %) was measured in IL-6 knockout (KO) animals. Turpentine treatment did not affect the expression of ANXA1 in either animal type. LPS enhanced serum c orticosteroid levels equally in WT and IL-6 KO mice, whereas higher tumor n ecrosis factor (TNF)-alpha and IL-1 beta levels were released in IL-6 KO an imals. Injection of mouse recombinant IL-6 to IL-6 KO animals before LPS or TNF-alpha challenge, replenished ANXA1 liver synthesis to that of WT anima ls. Exogenous ANXA1 but not ANXA5, administered to IL-6 KO mice before LPS challenge inhibited TNT-alpha release. We propose that ANXA1 acts as a nove l acute phase protein, which is controlled in the liver by TNF-alpha and IL -6, and which may contribute to the resolution of systemic endotoxemia thro ugh a negative feedback on TNF-alpha release.