Animals were divided into four groups. Rats in the control group were given IV saline injections at the acute and chronic phases. The other three groups of animals received IV injections of apoA-1 (the main apolipoprotein in HDL) either alone or in combination with saline at different time periods: a single treatment during either the acute or chronic phases of inflammation, or, as in group 4, injections of only apoA-1 during both the acute and chronic phases. Regardless of when the apoA-1 was administered, the injection produced a markedly reduced inflammatory response. The team also looked at T-cell and monocyte activation in all groups of animals. They found that, irrespective of the timing of the apoA-1 injection, the T-cell and monocyte counts were reduced nearly to baseline levels by the end of the experimental period (21 days from injection of PG-PS).
From these preliminary results, the team concluded that apoA-1 inhibits PG-PS–induced T-cell activation and cytokine production, and that it is effective in inhibiting joint inflammation in the Lewis rat. This study is part of an ongoing project, Dr. Rye noted, and her team has retained plasma and tissue samples from the animals to further test the levels of a list of chemokines to see whether the results hold. “We’re going to be looking much more closely at these markers and see if we can identify some of the pathways that are involved in mediating these effects,” she said.
Linking Cholesterol Transport and Inflammation
Uwe J. F. Tietge, MD, PhD, professor of pediatrics at the Center for Liver, Digestive, and Metabolic Diseases at the University Medical Center Groningen, The Netherlands, also spoke at the session. In his talk entitled, “Liver X Receptor Signaling at the Crossroads between Immunity and Cholesterol Homeostasis,” Dr. Tietge first summarized the large body of work on reverse cholesterol transport (RCT), a process mediated by LXR transcription. Liver X receptors (LXRs) function as nuclear cholesterol sensors that are activated in response to elevated intracellular cholesterol levels in multiple cell types.2 When LXRs are activated, they induce expression of an array of genes involved in cholesterol absorption, efflux, transport, and excretion. “Globally,” noted Dr. Tietge, “LXR activation coordinates the response to eliminate cholesterol from the body.” LXRα, the alpha isoform, is mainly expressed in the liver, intestine, kidney, adrenals, adipose tissue, and macrophages. The beta isoform of LXR (LXRβ) is more ubiquitously expressed.
LXR activation also increases the expression of antiinflammatory genes. The ability of LXRs to integrate metabolic and inflammatory signaling makes them potentially attractive targets for designing interventions in metabolic disease.
