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. 2007 May 25;357(1):319-24.
doi: 10.1016/j.bbrc.2007.03.150. Epub 2007 Apr 2.

Effects of apoE genotype on macrophage inflammation and heme oxygenase-1 expression

Laia Jofre-Monseny  1 , Agnieszka Loboda, Anika E Wagner, Patricia Huebbe, Christine Boesch-Saadatmandi, Alicja Jozkowicz, Anne-Marie Minihane, Jozef Dulak, Gerald Rimbach
Affiliations

Effects of apoE genotype on macrophage inflammation and heme oxygenase-1 expression

Laia Jofre-Monseny et al. Biochem Biophys Res Commun. .

Abstract

In order to gain a more comprehensive understanding of the aetiology of apolipoprotein E4 genotype-cardiovascular disease (CVD) associations, the impact of the apoE genotype on the macrophage inflammatory response was examined. The murine monocyte-macrophage cell line (RAW 264.7) stably transfected to produce equal amounts of human apoE3 or apoE4 was used. Following LPS stimulation, apoE4-macrophages showed higher and lower concentrations of tumour necrosis factor alpha (pro-inflammatory) and interleukin 10 (anti-inflammatory), respectively, both at mRNA and protein levels. In addition, increased expression of heme oxygenase-1 (a stress-induced anti-inflammatory protein) was observed in the apoE4-cells. Furthermore, in apoE4-macrophages, an enhanced transactivation of the key redox sensitive transcription factor NF-kappaB was shown. Current data indicate that apoE4 macrophages have an altered inflammatory response, which may contribute to the higher CVD risk observed in apoE4 carriers.

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Figures

Fig. 1
Fig. 1
Cytokine production in RAW 264.7-apoE3 and -apoE4 following stimulation with increasing concentrations of LPS (0–10 μg/ml) for 4 h. Supernatants were collected for ELISA analysis 20 h later. (A) IL1β, (B) MIP1α, (C) IL6, (D) TNFα, (E) IL10. Data are expressed as means ± SEM of three independent experiments performed in duplicate. ∗P < 0.05, ∗∗P < 0.01, comparing E3- vs. E4-cells at each LPS concentration.
Fig. 2
Fig. 2
Cytokine mRNA levels measured using reverse transcription real-time PCR in RAW 264.7-apoE3 and -apoE4 following stimulation with LPS (1 μg/ml) for 6 h or 1 h (TNFα). Results are calculated with the 2−ΔΔCt method and data are expressed as means ± SEM of three independent experiments performed in duplicate. ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001, comparing E3- vs. E4-cells at each LPS concentration.
Fig. 3
Fig. 3
(A) NF-κB activity detected with alkaline phosphatase reporter gene assay in RAW 264.7-apoE3 and -apoE4 following stimulation with increasing concentrations of LPS (0–1 μg/ml) for 6 h. (B) NF-κB activity following stimulation with LPS (0.1 μg/ml) for 6, 12, and 24 h. Results are calculated as chemiluminescence units corrected for total protein, and as fold change of apoE3 controls. Data are expressed as means ± SEM of three independent experiments performed in duplicate. ∗P < 0.05, ∗∗P < 0. 01, ∗∗∗P < 0.001 comparing E3- vs. E4-cells at each LPS concentration; (C) control non-stimulated cells.
Fig. 4
Fig. 4
(A) HO-1 mRNA levels detected with reverse transcription real-time PCR following stimulation with LPS (1 μg/ml) for 24 h. Results are calculated with the 2−ΔΔCt method and data is expressed as mean ± SEM of four independent experiments performed in duplicate. ∗P < 0.05, ∗∗∗P < 0.001, comparing E3- vs. E4-cells at each LPS concentration. (B) HO-1 levels as determined by Western blotting in relation to α-tubulin in RAW 264.7-apoE3 and -apoE4 under baseline conditions (control) and following stimulation with LPS (1 μg/ml) for 24 h.
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