title: Antithrombin acts as a negative acute phase protein as established with studies on HepG2 cells and in baboons.
abstract: Patients with sepsis or after major surgery have decreased plasma levels of the anticoagulant protein antithrombin. In such patients elevated levels of interleukin-6 (IL-6) are present and this interleukin is known to induce positive and negative acute phase responses. To investigate the possibility that antithrombin acts as a negative acute phase response-protein we performed studies on the human hepatoma cell line HepG2 in vitro and baboons in vivo. HepG2 cells were treated with recombinant human IL-6, IL-1beta, or combinations of the latter two, and tested for production of antithrombin, fibrinogen and prealbumin (transthyretin). This treatment resulted in a dose dependent increase in fibrinogen concentration (with a maximum effect of 2.8-2.9-fold) and a dose dependent decrease in prealbumin (with a maximum effect of 0.6-0.7-fold) and antithrombin concentrations (with a maximum effect of 0.6-0.8-fold). Simultaneous treatment of the HepG2 cells with IL-6 (1,000 pg/ml or 2,500 pg/ml) and IL-1beta (25 pg/ml), provided more extensively decreased prealbumin (0.8 and 0.6-fold, respectively) and antithrombin concentration (0.7 and 0.6-fold, respectively) compared to the single interleukin treatment at these concentrations. Baboons treated with 2 microg IL-6 x kg body-weight(-1) x day(-1) showed increased plasma CRP levels (59-fold, p <0.05) and decreased prealbumin (0.9-fold, p <0.05) and antithrombin (0.8-fold, p <0.05) plasma levels, without evidence for coagulation activation. Our results indicate that antithrombin acts as a negative acute phase protein, which may contribute to the decreased antithrombin plasma levels observed after major surgery or in sepsis.
authors.affiliation: Center for Hemostasis, Thrombosis, Atherosclerosis and Inflammation Research, Amsterdam, The Netherlands.
authors.forename: R W
authors.initials: RW
authors.lastname: Niessen
authors.forename: R J
authors.initials: RJ
authors.lastname: Lamping
authors.forename: P M
authors.initials: PM
authors.lastname: Jansen
authors.forename: M H
authors.initials: MH
authors.lastname: Prins
authors.forename: M
authors.initials: M
authors.lastname: Peters
authors.forename: F B
authors.initials: FB
authors.lastname: Taylor
authors.forename: J J
authors.initials: JJ
authors.lastname: de Vijlder
authors.forename: J W
authors.initials: JW
authors.lastname: ten Cate
authors.forename: C E
authors.initials: CE
authors.lastname: Hack
authors.forename: A
authors.initials: A
authors.lastname: Sturk
mesh_terms: D000210:Acute-Phase Reaction; D000818:Animals; D000990:Antithrombin III / Q000096:biosynthesis*; D002097:C-Reactive Protein / Q000096:biosynthesis; D006528:Carcinoma, Hepatocellular; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D010215:Papio; D011228:Prealbumin / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000378:metabolism
chemical_list: D007375:Interleukin-1; D015850:Interleukin-6; D011228:Prealbumin; D011994:Recombinant Proteins; D000990:Antithrombin III; D002097:C-Reactive Protein