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Augmented levels of CD44 in macrophages from atherosclerotic subjects: a possible IL-6-CD44 feedback loop?
Daniel Hägg1, Sara Sjöberg, Lillemor Mattsson Hultén
1Research Center for Endocrinology and Metabolism, Department of Metabolism and Cardiovascular Research, Göteborg, Sweden.
Insights
Elevated CD44 levels in macrophages are linked to atherosclerosis. Interleukin-6 (IL-6) and CD44 form a feedback loop, potentially worsening this cardiovascular disease.
Area of Science:
- Immunology
- Cardiovascular Biology
- Molecular Biology
Background:
- The cell-adhesion molecule CD44 is implicated in atherosclerosis.
- Pro-inflammatory cytokines are known to influence CD44 expression.
Purpose of the Study:
- To investigate the role of elevated CD44 levels in human macrophages within the context of atherosclerosis.
- To explore the relationship between CD44 expression, genetic factors, and cytokine levels in atherosclerotic subjects.
Main Methods:
- Compared CD44 transcript and protein levels in macrophages from atherosclerotic subjects versus controls.
- Analyzed single nucleotide polymorphisms in the CD44 gene for association with coronary artery disease.
- Examined correlations between plasma cytokine levels and CD44 expression.
- Investigated IL-6 levels in CD44-deficient mice and the effect of IL-6 on CD44 expression in human macrophages.
Main Results:
- Macrophages from atherosclerotic subjects exhibited significantly elevated CD44 transcript and protein levels.
- No association was found between analyzed CD44 gene polymorphisms and coronary artery disease.
- Elevated CD44 expression in atherosclerotic subjects correlated with increased IL-6 secretion.
- CD44-deficient mice showed reduced circulating IL-6 levels.
- IL-6 was found to augment CD44 expression in human macrophages over time.
Conclusions:
- A positive feedback loop exists between IL-6 and CD44 in macrophages.
- This IL-6-CD44 feedback loop may contribute to the progression of atherosclerosis.
Abstract:
The cell-adhesion molecule CD44 likely participates in atherosclerosis development. We have shown previously that pro-inflammatory cytokines affect CD44 expression. Therefore, this work examined the role of elevated CD44 levels in human macrophages. Macrophages from human atherosclerotic subjects (n=15) showed elevated levels of CD44 transcript and protein (1.5-fold) compared to matched controls (n=15) (P=0.050 and 0.044, respectively). To test whether genetic factors influence CD44 expression, two single nucleotide polymorphisms in the CD44 gene were analyzed but these were not associated with coronary artery disease. We also examined the potential connection between plasma cytokine levels and CD44 expression. In atherosclerotic subjects, elevated CD44 expression correlates (P=0.012) with enhanced macrophage IL-6 secretion (3.13+/-2.5 pg/mL versus 0.32+/-0.16 pg/mL in controls, P=0.021). Additionally, CD44-deficient mice exhibit less circulating IL-6 than wild-type controls (9.8+/-0.7 pg/mL versus 14.3+/-0.7 pg/mL; P=0.032). Furthermore, IL-6 augments CD44 expression in primary human macrophages after 24 h (P=0.038) and 48 h (P=0.015). Taken together, our data show an IL-6-CD44 feedback loop in macrophages. Such a positive feedback loop may aggravate atherosclerosis development.
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