World Journal of Cardiovascular Diseases, 2014, 4, 416-421

Published Online August 2014 in SciRes. http://www.scirp.org/journal/wjcd

http://dx.doi.org/10.4236/wjcd.2014.49052

Clinical Implications of Tumor Necrosis

Factor-Alpha, Interleukin-6 and Resistin
in Coronary Artery Disease
Qamar Javed
Department of Biochemistry, Quaid-i-Azam University, Islamabad, Pakistan
Email: qjaved6@gmail.com

Received 23 May 2014; revised 5 June 2014; accepted 1 July 2014

Copyright © 2014 by author and Scientific Research Publishing Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY).
http://creativecommons.org/licenses/by/4.0/

Abstract
Tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) are involved in the progression
of coronary artery disease (CAD). The cytokines’ levels are associated with the severity of CAD. We
have recently reported on the association of resistin, a relatively novel cytokine with the patho-
genesis of cardiovascular disease (CVD). Although the inflammatory cytokines’ impact on atheros-
clerosis is widely accepted, yet some controversy exists regarding the involvement of these factors
in atherogenesis. The current review highlights the potential association of TNF-alpha, IL-6 and
resistin SNPs (single nucleotide polymorphisms) with CAD. Molecular genetics data along with the
intracellular signaling cascade mechanisms may have important clinical implications in the treat-
ment of CAD.

Keywords
Tumor Necrosis Factor-Alpha, Interleukin-6, Resistin, Coronory Heart Disease, Gene
Polymorphism

1. Atheroma Formation and Inflammation

Cardiovascular disease (CVD) has gradually become one of the major causes of death worldwide. Atherosclero-
sis and resulting clinical complications are complex pathophysiologic processes involving a variety of genes and
gene products in complicated interactions with environmental influences [1]. According to the WHO health re-
port 2008, global estimates of mortality due to CVD are predicted to rise from 17.1 million in 2004 to 23.4 mil-
lion in 2030. A range of genetic and environmental factors appear to participate in the pathogenesis of coronary
artery disease (CAD). A number of cardiovascular risk factors and other markers of cardiac stress and malfunc-
tion, as well as myocyte injury appear to have growing clinical importance. Some cardiovascular biomarkers

How to cite this paper: Javed, Q. (2014) Clinical Implications of Tumor Necrosis Factor-Alpha, Interleukin-6 and Resistin in
Coronary Artery Disease. World Journal of Cardiovascular Diseases, 4, 416-421. http://dx.doi.org/10.4236/wjcd.2014.49052
 Q. Javed

could be risk factors themselves and therefore may be potential targets of therapy [2]. A role for inflammation
has become well established in the development of CAD over the past couple of decades. In particular, in-
flammatory responses to arterial injury resulted in the recruitment and activation of monocytes mainly through
activation of the monocyte chemoattractantprotein-1 (MCP-1) pathway have a central role in atherogenesis [3].
Atherosclerotic lesions are asymmetric focal thickenings of the innermost layer of the artery consisting of cells,
connective-tissue elements, lipids, and debris [4]. In addition to these components, blood borne inflammatory
and immune cells along with vascular endothelial and smooth-muscle cells constitute an important part of the
atheroma. There is a close relation between atherogenesis and inflammation. Inflammatory mediators are found
to be not only responsible for the contribution to the atheroma formation, but may also affect in the rapid evolu-
tion of the atheromatous injury, leading to plaque rupture, nitrous oxide production and thrombosis. In this sense,
it is worth noting that several cytokines may play a role in determining the degree of inflammation and contri-
buting to atherogenesis [5]. Thus, from a pathological perspective, initiation, growth, and complication of the
atherosclerotic plaque, may be considered as an inflammatory response to injury [6]. While traditional risk fac-
tors still prevail, newer risk factors are also emerging.

2. Tumor Necrosis Factor-Alpha

The inflammatory cytokine, TNF-alpha, is considered to play a role in the development of CVD [7] [8]. The
over expression of TNF-alpha has been implicated in the pathogenesis of several conditions including arthritis,
CAD and myocardial dysfunction [9] [10]. TNF-alpha is known to exert a range of inflammatory and immuno-
modulatory activities in vivo. Currently, the focus is on the mechanisms that modulate TNF-alpha production,
which in turn impact on the inflammation-mediated disease process. Various polymorphisms have been identi-
fied within and around the TNF-alpha encoding gene located within the major histocompatibility complex
(MHC). In the promoter region relative to the transcription start site, there are several single nucleotide poly-
morphisms (SNPs), at positions −1031 (T*C), −863 (C*A), −857 (C*A), −851 (C*T), −419 (G*C), −376 (G*A),
−308 (G*A), −238 (G*A), and −163 (G*A). A single gene polymorphism could contribute to the overall risk of
cardiovascular events. Polymorphisms at position −308 (G*A) and −238 (G*A) have been shown to be asso-
ciated with CVD [11]. Cardiovascular complications may be influenced by TNF-alpha gene polymorphisms [12].
Elevated TNF-alpha levels have consistently been reported in patients with heart failure and increasing concen-
trations of the cytokine are related with the severity of CVD and mortality rate in the patients [13] [14]. Some of
the TNF-alpha gene polymorphisms have direct effect on gene transcription and protein function. However, cer-
tain studies failed to find a significant association between the TNF-alpha gene polymorphisms and CVD [15]
[16]. Further in-depth studies and haplotype analysis are required to resolve this controversy.

3. Interleukin-6
The molecular mechanisms involved in the pathogenesis of CAD are still not fully understood. However, there
is a consensus that the main events of unstable angina and myocardial infarction are due to the involvement of
major inflammatory cytokines. Besides TNF-alpha, IL-6 also has a significant role in the development of CAD.
IL-6 is associated with the process of inflammation, and it up-regulates the synthesis of the acute phase proteins
involved in the process of inflammation [17]. Several reports have linked systemic inflammation and CVD [18].
Patients with high levels of IL-6 show a worse in-hospital outcome following treatment in case of unstable an-
gina [19] [20]. Cardiovascular risk factors like smoking and physiological stress increase the levels of IL-6 in
plasma [21] [22]. IL-6 expression may determine the magnitude of inflammation and its correlation with CVD.
The major breakthrough of IL-6 gene polymorphism has been shown to determine the levels of IL-6 production
in the body [23]. An association has been shown between the IL-6 promoter polymorphism −174G/C and left
ventricular hypertrophy (LVH) and hypertension in patients [24]. This polymorphism also shows association
with CAD [25]. IL-6 gene polymorphisms (−174G > C, −572G > C and −597G > A) are strong predictors of the
cytokine concentrations in plasma following inflammatory stimulus, which is clinically relevant in patients with
CVD [26].

4. Resistin
Recent investigations have highlighted the involvement of a novel cytokine, resistin, in the pathogenesis of CVD

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Q. Javed

[27] [28]. The resistin gene (RETN) polymorphism at −420 and +299 leads to increased concentrations of the
peptide in circulation, which is associated with cardiomyopathy and CAD. CVD patients with the RETN variant
alleles, in addition to elevated inflammatory markers resistin and high sensitivity C-reactive protein, showed
significantly high levels of primary risk factors e.g. total cholesterol, low-density lipoprotein, triglycerides and
low concentrations of high-density lipoprotein. It appears that besides primary risk factors, resistin cytokine may
be a risk factor for CVD. Taken together these risk factors could have a pronounced effect on cardiovascular
pathology.
CVD history is another risk factor of the disease. Evidence shows that there is an increased risk of coronary
complications in healthy siblings of patients with CAD [28]. Interestingly, healthy subjects from families with

Figure 1. Intracellular signaling pathway. Mitogenic factors and oxidative stress activate the CD 14 receptor to induce cy-
tokines expression (e.g. TNF, IL-6 and resistin). These stimuli lead to tyrosine phosphorylation of Ras by phosphotyrosine
kinase (PTK); the protein kinase cascade leads to cytokines’ production. Ras activates Raf-1/mitogen-activated protein ki-
nase, followed by the activation of the mitogen-activated protein kinase (MAPK) family of protein kinases, extracellular
signal-related kinase (ERKs), stress-activated protein kinase (SAPK), and jun nuclear kinase (JNK) and the P38 MAPK.
NFκB is activated by phosphorylation and translocates to the nucleus to activate promoter sites.

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CAD history had a higher frequency of the RETN −420G variant allele [28] compared with the individuals
without disease history [6]. It is probable that the disease-susceptible alleles among healthy subjects may pre-
dispose them to the disease. Genetic makeup can influence the disease pathology as evidenced from a cross-
sectional study demonstrating lowest rates of CVD from the Chinese Canadians compared with European Cana-
dians with the moderate disease rates [29].

5. Role of Cytokines Signaling Pathway in CAD

Intracellular signaling pathways propagate downstream events in the regulation of gene expression. A functional
genetic variant in the promoter region of the above mentioned inflammatory markers may affect the cytokines’
levels via the p38 mitogen-activated protein kinase (p38 MAPK) signaling involving nuclear factor kappa B
(NFκB) cascade loop (Figure 1). Hence from this aspect, SNPs may lead to elevated gene expression of in-
flammatory cytokines which could influence clinical outcome in patients with CAD. Molecular mechanisms that
provide insights into the role of inflammatory markers have been a focus of immense interest in recent studies.
Genome-wide association studies (GWAS) indicate that SNPs on 9p21 (Chr9p21) contribute to susceptibility of
CAD [30]-[32]. Cytokines’ haplotypes comprising of CAD-susceptible alleles could significantly affect the dis-
ease pathophysiology by up-regulating the inflammatory markers expression. Furthermore, evidence shows that
methylation of P15INK4B appears to be involved in the pathogenesis of CAD [33]. This suggests that promoter
region methylation is another factor that may influence gene expression. Since less information is available re-
garding post-transcriptional regulation of candidate genes of CAD, further studies from this perspective may
help in elucidating the molecular basis of the disease pathology. A better understanding of the genetic control of
the inflammatory processes could have useful clinical implications. Genetic makeup of patients determines the
clinical outcome in response to the disease treatment [34]. Molecular investigations based on the disease-sus-
ceptible genes and their pathophysiological influences on the pathogenesis of the disease are warranted to limit
CAD and other CVD complications which are currently increasing globally.

Acknowledgements
Cytokines study in our laboratory was supported by the Pakistan Science Foundation and the Higher Education
Commission of Pakistan.

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