Ultrasound Biomicroscopic Imaging for Interleukin-1 Receptor Antagonist–Inhibiting Atherosclerosis and Markers of Inflammation in Atherosclerotic Development in Apolipoprotein-E Knockout Mice

We sought to validate the hypothesis that the development of atherosclerosis can be suppressed by the interleukin-1 receptor antagonist (IL-1Ra) in murine models of atherosclerosis in vivo, noninvasively seen by means of high-resolution ultrasound biomicroscopy, and we studied changes in inflammatory markers such as IL-1 and C-reactive protein (CRP) plasma levels in these models of atherosclerosis. We divided IL-1Ra+/−/apolipoprotein-E (apoE)−/− and IL-1Ra+/+/apoE−/− mice into 2 age groups, used as atherosclerotic models. The control groups were age-matched IL-1Ra+/+/apoE+/+ mice. Plaque thickness was measured in the ascending aorta in short-axis images by means of ultrasound and histology. Plasma levels of IL-1 and CRP were quantified in the 3 murine groups. At 16 weeks, plaque thickness in the ascending aortas of the IL-1Ra+/−/apoE−/− mice was significantly greater than that in the IL-1Ra+/+/apoE−/− mice, on ultrasound and histology (P <0.01). In contrast, at 32 weeks, the differences between these 2 genotypes were not statistically significant. Serum IL-1 levels were lower in the IL-1Ra+/−/apoE−/− mice than in the IL-1Ra+/+/apoE−/− mice at 16 and 32 weeks (P <0.05). At 16 weeks, serum CRP levels in the IL-1Ra+/−/apoE−/− mice were higher than in the IL-1Ra+/+/apoE−/− mice (P <0.01). Our results suggest that ultrasound biomicroscopy enables evaluation of atherosclerotic lesions in vivo, noninvasively and in real-time, in apoE−/− mice. Partial IL-1Ra deficiencies might promote early plaque development in 16-week-old apoE−/− mice. The balance of IL-1 and IL-1Ra might influence atherosclerotic development. Finally, CRP might affect the initiation of atherosclerosis, rather than its progression.

Download Full-text

Release of cytokines, soluble cytokine receptors, and interleukin-1 receptor antagonist after intravenous immunoglobulin administration in vivo

Blood ◽

10.1182/blood.v84.7.2136.2136 ◽

1994 ◽

Vol 84 (7) ◽

pp. 2136-2143 ◽

Cited By ~ 141

Author(s):

P Aukrust ◽

SS Froland ◽

NB Liabakk ◽

F Muller ◽

I Nordoy ◽

...

Keyword(s):

Receptor Antagonist ◽

Intravenous Immunoglobulin ◽

Plasma Levels ◽

Interleukin 1 ◽

Cytokine Receptors ◽

Tnf Alpha ◽

Ivig Infusion ◽

Molar Excess ◽

Interleukin 1 Receptor Antagonist

Abstract We investigated the in vivo effects of one bolus injection (400 mg/kg) of intravenous immunoglobulin (IVIG) on a number of cytokines, soluble cytokine receptors, and interleukin-1 receptor antagonist (IL-1Ra) in plasma in 12 patients with primary hypogammaglobulinemia. A significant and rapid increase in plasma levels of IL-6, IL-8, and tumor necrosis factor alpha (TNF alpha) was seen within 1 hour after IVIG infusion. This increase was accompanied by a more prolonged elevation in levels of both types of soluble TNF receptors (sTNFRs), which remained elevated throughout the study period (44 hours) although they reached peak levels within 1 hour. After an initial increase in the ratio between TNF alpha and sTNFRs, this ratio decreased to values significantly lower than baseline values 20 and 44 hours postinfusion with approximately 600-fold molar excess of sTNFRs to TNF alpha (trimer). Although only a modest but statistically significant increase in plasma levels of IL-1 beta was seen, IVIG infusion was followed by a marked increase in plasma levels of IL-1Ra with 1,000-fold molar excess of IL-1Ra to IL-1 beta in some patients. The demonstrated effects of IVIG infusion on the cytokine network, particularly the induction of IL- 1Ra and sTNFRs release, might be important for the therapeutic effects of IVIG in several immune-mediated disorders.

Download Full-text

Release of cytokines, soluble cytokine receptors, and interleukin-1 receptor antagonist after intravenous immunoglobulin administration in vivo

Blood ◽

10.1182/blood.v84.7.2136.bloodjournal8472136 ◽

1994 ◽

Vol 84 (7) ◽

pp. 2136-2143 ◽

Cited By ~ 2

Author(s):

P Aukrust ◽

SS Froland ◽

NB Liabakk ◽

F Muller ◽

I Nordoy ◽

...

Keyword(s):

Receptor Antagonist ◽

Intravenous Immunoglobulin ◽

Plasma Levels ◽

Interleukin 1 ◽

Cytokine Receptors ◽

Tnf Alpha ◽

Ivig Infusion ◽

Molar Excess ◽

Interleukin 1 Receptor Antagonist

We investigated the in vivo effects of one bolus injection (400 mg/kg) of intravenous immunoglobulin (IVIG) on a number of cytokines, soluble cytokine receptors, and interleukin-1 receptor antagonist (IL-1Ra) in plasma in 12 patients with primary hypogammaglobulinemia. A significant and rapid increase in plasma levels of IL-6, IL-8, and tumor necrosis factor alpha (TNF alpha) was seen within 1 hour after IVIG infusion. This increase was accompanied by a more prolonged elevation in levels of both types of soluble TNF receptors (sTNFRs), which remained elevated throughout the study period (44 hours) although they reached peak levels within 1 hour. After an initial increase in the ratio between TNF alpha and sTNFRs, this ratio decreased to values significantly lower than baseline values 20 and 44 hours postinfusion with approximately 600-fold molar excess of sTNFRs to TNF alpha (trimer). Although only a modest but statistically significant increase in plasma levels of IL-1 beta was seen, IVIG infusion was followed by a marked increase in plasma levels of IL-1Ra with 1,000-fold molar excess of IL-1Ra to IL-1 beta in some patients. The demonstrated effects of IVIG infusion on the cytokine network, particularly the induction of IL- 1Ra and sTNFRs release, might be important for the therapeutic effects of IVIG in several immune-mediated disorders.

Download Full-text