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Interleukin-6, C-reactive Protein and Coronary Heart Disease

Posted by plosmedicine on 30 Mar 2009 at 05:24 GMT

Author: irving kushner
Position: Professor of Medicine
Institution: Case Western Reserve University, MetroHealth Campus
E-mail: ikushner@metrohealth.org
Submitted Date: April 10, 2008
Published Date: April 11, 2008
This comment was originally posted as a “Reader Response” on the publication date indicated above. All Reader Responses are now available as comments.

The findings reported by Danesh et al (1) highlighting the potential relevance of IL-6 – mediated pathways to coronary heart disease (CHD) are comparable to the abundantly reported association between serum C-reactive protein (CRP) levels and CHD. This is not surprising, since IL-6 is the cytokine primarily responsible for CRP induction. IL-6 levels correlate with CRP levels in most conditions studied, and CRP and IL-6 are both associated with the same conditions (and CHD risk factors): smoking, hypertension, dyslipidemia, etc.

As the accompanying Perspective by Neal (2) correctly points out, known risk factors account for over 90% of cases of CHD (3). All of the critically implicated risk factors have been reported to be associated with at least minor CRP elevation, as have a number of other conditions and dietary patterns associated with poor health (4). We now realize that all tissues contain sentinel cells, of several types, that vigilantly monitor the environment for evidence of sublethal tissue injury or cellular distress (5). When such evidence is found, they produce inflammatory mediators. It is thus not unexpected that minor degrees of tissue injury would be accompanied by elevated IL-6 levels and a minor CRP response.

So why do IL-6 and CRP predict CHD? This scenario, that tissue injury causes IL-6 production with consequent CRP induction, would indicate that serum IL-6 and CRP levels are reflectors rather than effectors. They inform us of the presence of distressed cells. This conclusion argues, as Neal has persuasively done, against the utility of identifying IL-6 as a therapeutic target.

The Editors’ Summary explicating the article by Danesh et al deserves comment. Did the editors really mean that “increased long-term IL-6 levels more than doubled the risk for CHD”, which implies causality, or did they mean that increased IL-6 levels were associated with a more than doubled risk, which is what the authors actually showed?

References

1. Danesh J, K. S., Mann AG, Sarwar N, Wood A, et al. (2008) PLoS Medicine 5, e78 doi:10.1371/journal.pmed.0050078
2. Neal, B. (2008) PLoS Medicine 5, e84 doi:10.1371/journal.pmed.0050084
3. Yusuf, S., Hawken, S., Ounpuu, S., Dans, T., Avezum, A., et al. (2004) Lancet 364, 937-952.
4. Kushner, I., Rzewnicki, D., and Samols, D. (2006) Am J Med 119, 166 e117-128
5. Linde, A., Mosier, D., Blecha, F., and Melgarejo, T. (2007) Cardiovasc Res 73, 26-36

No competing interests declared.