Chylomicron-bound LPS inhibits activation of the acute phase response in vitro and in vivo

Abstract

The host response to infection involves the release of multiple pro-inflammatory cytokines. These soluble mediators (e.g., TNF-α, IL-6) not only promote an acute inflammatory reaction, but also activate a dramatic change in hepatic gene expression termed the acute phase response (APR). This cytokine-mediated alteration in hepatocellular function includes changes in the activity of CCAAT/enhancer binding protein (C/EBP), an IL-6 response element that regulates many APR genes. We have previously shown the CM-bound LPS (CM-LPS) modulates the hepatocellular response to infection by inhibiting cytokine-induced NF-kB activity and NO production. Thus, we hypothesize that CM-bound LPS can similarly inhibit the IL-6-mediated activation of the APR in vitro and in vivo. For in vitro studies, rat primary hepatocytes were pretreated with or without CM-LPS and stimulated with 500 units/ml of IL-6. To enhance the IL-6 response, 1 μM dexamethasone was also added. Hepatic nuclear C/EBP was measured at 15 min and 24h after stimulation. For in vivo studies, rats were injected with CM-LPS (235 mg/kg, pre-treated) v. saline (control), recovered for 16h and then injected with IL-6 (2.6 × 105 U/kg) to induce an APR. Hepatic nuclear C/EBP and plasma LBP levels were measured at 4h and 24h after IL-6 stimulation. Pretreatment with CM-LPS markedly inhibited hepatic C/EBP activity at 15 min and 24h in vitro and at both 4 and 24h in vivo (data not shown) as compared to controls (Fig. 1). In summary, pretreatment with CM-LPS significantly inhibited activation of the APR in vitro and in vivo as measured by C/EBP activity. These data add to a growing body of evidence implicating lipoproteins as important regulators of the host immune response to bacterial infection.