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(Circulation Research. 2006;98:e26.)
© 2006 American Heart Association, Inc.

Letter to the Editor

FcIIB and Cardiovascular Inflammatory Disease

Chiharu Kishimoto, Keisuke Shioji, Zuyi Yuan

Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan

To the Editor:

We read with great interest the article by Mineo and colleagues¹ exploring the role of FcIIB, an inhibitory receptor of FcIIs, on C-reactive protein (CRP)-mediated endothelial dysfunction. Mineo et al examined the mechanisms of CRP actions on endothelium by testing the hypothesis that CRP attenuates endothelial NO synthase (eNOS) activation in vitro. The investigators found that CRP-induced declines in NO production promote monocyte adhesion to endothelium. They further investigated the role of Fc receptors, which display high affinity for CRP and modulate CRP actions. They found that, in FcRIIB^+/+ mice, CRP blunts acetylcholine-induced increases in carotid artery vascular conductance, and that, in contrast, CRP enhances acetylcholine responses in FcRIIB^–/– mice. They concluded that FcRIIB mediates CRP inhibition of eNOS.

At first glance, their results appear to be contradictory to previous reports by our own group^2,3 and by Gill et al.⁴ In our study, not only FcRIIB-mediated inhibitory effect on experimental autoimmune myocarditis in rats² but FcRIIB-mediated antiatherosclerotic effect in apolipoprotein E–deficient mice³ were demonstrated, using immunoglobulin preparations. Gill et al⁴ demonstrated the targeting effect of immunoglobulin on adhesion molecules using ischemia–reperfusion model in cats, suggesting the downregulation of adhesion molecules via Fc receptors.

The fact that FcRIIB mediates CRP inhibition of eNOS, resulting in endothelial dysfunction, is not necessarily in contradiction to aforementioned studies from different groups.^2–4 The precise effect of FcRIIB on cardiovascular inflammatory cascades may depend on experimental models. Such opposite activatory and inhibitory actions of FcRIIB against inflammation may occur, depending on the dose used and the experimental conditions. In fact, there are FcRIIA, an activatory receptor, and FcRIIB, an inhibitory receptor, in humans, but only FcRIIB has been identified in mice.⁵

Mineo et al¹ also explored the fact that FcRIIB is expressed in human endothelial cells and in mouse endothelium. It is well known that CRP levels are strongly correlated with increased risk for cardiovascular inflammatory diseases.^6,7 Taken together, they proposed a CRP-modulating novel therapy by FcRIIB for preventing cardiovascular complications in multiple inflammatory and autoimmune disorders. We agree with their proposal, because of the great pathogenetic contribution of FcIIs in cardiovascular inflammatory diseases.

References

1. Mineo C, Gormley AK, Yuhanna IS, Osborne-Lawrence S, Gibson LL, Hahner L, Shohet RV, Black S, Salmon JE, Samols D, Karp DR, Thomas GD, Shaul PW. FcRIIB mediates C-reactive protein inhibition of endothelial NO synthase. Circ Res. 2005; 97: 1124–1131.[Abstract/Free Full Text]
2. Shioji K, Kishimoto C, Sasayama S. Fc receptor-mediated inhibitory effect of immunoglobulin therapy on autoimmune giant cell myocarditis. Concomitant suppression of the expression of dendritic cells. Circ Res. 2001; 89: 540–546.[Abstract/Free Full Text]
3. Yuan Z, Kishimoto C, Sano H, Shioji K, Xu Y, Yokode M. Immunoglobulin treatment suppresses atherosclerosis in apolipoprotein E-deficient mice via the Fc portion. Am J Physiol Heart Circ Physiol. 2003; 285: H899–H906.[Abstract/Free Full Text]
4. Gill V, Doig C, Knight D, Love E, Kubes P. Targeting adhesion molecules as a potential mechanism of action for intravenous immunoglobulin. Circulation. 2005; 112: 2031–2039.[Abstract/Free Full Text]
5. Ravetch JV, Bolland S. IgG Fc receptors. Annu Rev Immunol. 2001; 19: 275–290.[CrossRef][Medline] [Order article via Infotrieve]
6. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002; 347: 1557–1565.[Abstract/Free Full Text]
7. Schwedler SB, Amann K, Wernicke K, Krebs A, Nauck M, Wanner C, Potempa LA, Galle J. Native C-reactive protein increases whereas modified c-reactive protein reduces atherosclerosis in apolipoprotein E-knockout mice. Circulation. 2005; 112: 1016–1023.[Abstract/Free Full Text]

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