No abstract

Rationale: Macrophages cannot limit the uptake of lipids and rely on cholesterol efflux mechanisms for maintaining cellular cholesterol homeostasis. Important mediators of macrophage cholesterol efflux are ATP-binding cassette transporter 1 (ABCA1), which mediates the efflux of cholesterol to lipid-poor apolipoprotein AI, and scavenger receptor class B type I (SR-BI), which promotes efflux to mature high-density lipoprotein. Objective:The aim of the present study was to increase the insight into the putative synergistic roles of ABCA1 and SR-BI in foam cell formation and atherosclerosis. ABCA1 is a full-size ABC-transporter that facilitates cholesterol efflux to lipid-poor apolipoprotein (apo)AI. 2,3 Totalbody ABCA1 knockout mice and Tangier disease patients with dysfunctional ABCA1 display a virtual absence of high-density lipoprotein (HDL), showing the essential role for ABCA1 in HDL metabolism. 3 Targeted inactivation of ABCA1 in bone marrow-derived cells in mice leads to increased atherosclerotic lesion formation, 4,5 whereas overexpression of ABCA1 inhibits the progression of atherosclerosis. 6 Macrophages lacking ABCA1, however, still have substantial ability to efflux cholesterol to HDL despite impaired efflux to lipid-poor apoAI, suggesting that macrophages have additional pathways via which cellular cholesterol can be exported. In addition to ABCA1, macrophages also express the ABC half-transporter ABCG1. In contrast to ABCA1, ABCG1 facilitates cellular cholesterol efflux from macrophages to mature HDL but not to lipid-free apolipopro- Methods and Results:

Interferon‐γ (IFN‐γ) receptor knock‐out (IFN‐γR−/−) mice were used to analyse the role of IFN‐γ in mucosal immune responses following oral immunization. We found that the IFN‐γR−/− mice demonstrated 50% reduced spot‐forming cell (SFC) responses in the gut lamina propria and spleen after oral immunization with keyhole limpet haemocyanin (KLH) plus cholera toxin (CT) adjuvant. The IFN‐γR−/− mice exhibited 10‐fold reduced total serum KLH‐specific antibody levels compared with wild‐type mice after oral immunization, while after intravenous immunization, no such difference was seen, suggesting a selective impairment of mucosal immune responses. Moreover, oral immunizations resulted in impaired interleukin‐4 (IL‐4), IL‐10 and IFN‐γ production by spleen T cells from IFN‐γR−/− mice, indicating that no reciprocal up‐regulation of Th2‐activities had occurred despite the lack of IFN‐γR function. No reduction in Th1 or Th2 cytokines was observed following systemic immunizations. Despite potentially strong modulating effects of IFN‐γ on epithelial cell IgA transcytosis and electrolyte barrier functions, CT‐immunized IFN‐γR−/− mice demonstrated unaltered protection against CT in ligated intestinal loops together with normal anti‐CT IgA and total IgA levels in gut lavage. Oral feeding with KLH followed by parenteral immunization resulted in strongly suppressed SFC numbers and reduced cell‐mediated immunity in both wild‐type and IFNγR−/− mice. CT‐adjuvant abrogated induction of oral tolerance in both IFN‐γR−/− and wild‐type mice. Collectively, our data argue that the two major response patterns induced by oral administration of protein antigen, i.e. active IgA immunity and oral tolerance, are differently regulated. Thus, IFN‐γR−/− mice have impaired mucosal immune responses while induction of oral tolerance appears to be unaffected by the lack of IFN‐γ functions.