Proinflammatory and atherogenic activity of monocytes in Type 2 diabetes

https://doi.org/10.1016/j.jdiacomp.2008.07.001Get rights and content

Abstract

Cytokines secreted by the monocyte–macrophage system play a key role in the progression of atherosclerotic lesions in Type 2 diabetes. The objectives of this study were to assess the influence of cytokine gene expression in monocytes from patients with Type 2 diabetes on direct markers of endothelial injury with regard to clinically manifest atherosclerosis.

Methods

Monocytes from 58 patients with Type 2 diabetes and from 22 age-matched healthy volunteers of a control group were isolated in order to assess expression of tumor necrosis factor α (TNFα), interleukin (IL)-6, IL-8 and IL-10 cytokines (RTPCR, Applied Biosystems). Thrombomodulin concentration was determined using a Diagnostica Stago Immunoenzymatic assay, and circulating endothelial cell numbers were assayed using immunofluorescence studies with CLB-HEC19 antibodies.

Results

In 28 patients, TNFα expression in monocytes was observed. In these patients, as compared to those with undetectable levels of this cytokine's expression, higher hemoglobin A1c (P=.012) and thrombomodulin (P=.005) concentrations were found. IL-8 expression was determined in 36 patients. Higher expression of TNFα (P=.048) and IL-8 (P=.049) was detected in patients with peripheral arterial disease in contrast to those free from this complication.

Conclusion

TNFα and IL-8 play a significant role in the proatherogenic activity of monocytes in Type 2 diabetes. The TNFα-connected activity of monocytes may directly determine endothelial dysfunction and injury. The location of atherosclerosis should be taken into account in the assessment of the proinflammatory activity of peripheral blood monocytes.

Introduction

Atheromatosis is the leading cause of incidence and preterm mortality in industrialized societies. Contemporary therapeutic programs do not sufficiently protect patients from the consequences of cardiovascular disease complications. Patients with coexistence of multiple proatherogenic factors, which promote chronic activation of inflammatory processes, such as: hyperglycaemia, insulin resistance, dyslipidemia, are especially at risk of developing quickly progressing atherosclerosis (Huang et al., 2002, Plutzky et al., 2002). For instance, Patino et al. (2000) determined that even in diabetic patients free from macroangiopathy, increased expression of receptors for monocyte CD14 lipopolysaccharide is observed. Meanwhile, Shanmugam et al. (Shanmugam, Reddy, Guha, & Natarajan, 2003) noted an in vitro increase in cytokine and chemokine expression, as well as vascular permeability increasing factors in response to hyperglycemia in monocytes. Moreover, Cipolletta, Ryan, Hanna, & Trimble (2005) demonstrated an increase in monocyte adhesion to the vessel wall in association with insufficient diabetic control. Recent studies highlight the key role of humoral factors in the pathobiology of atherosclerosis. Among these, tumor necrosis factor α (TNFα) is the most significant—recruiting different types of cells into the inflammatory process (Fernandez-Real & Ricart, 2003). Vendrell et al. (2003) noted that the TNFα-308 polimorphic variant in patients with Type 2 diabetes is linked with higher cardiovascular risk. Interleukin (IL)-6 is another important proatherogenic cytokine, multiplying cardiovascular risk even up to 1.1–3.1 times (Mostafa Mtairag et al., 2001). Polymorphic variants for this cytokine, which may promote susceptibility to atherosclerosis development, were also found (Flex et al., 2002, Giacconi et al., 2004). Chemokines, including IL-8, are also a group of active substances, indispensable for the development of inflammatory processes. IL-8 is responsible for granulocyte/monocyte transmigration into the vessel wall (Boisvert, 2004). IL-10 and other anti-inflammatory cytokines, which may protect against atherosclerosis, should not be forgotten. Numerous studies suggest IL-10's contribution toward a reduction of plaque instability (Mostafa Mtairag et al., 2001, Tziakas et al., 2003, van Berkel et al., 2004). The aim of this study is to assess the expression of selected cytokines TNFα, IL-6, IL-8 and IL-10 in peripheral blood monocytes of patients with insulin-resistance and diabetic macroangiopathy within the context of chosen proatherogenic parameters and direct markers of endothelial injury in Type 2 diabetes.

Section snippets

Materials and methods

The study was conducted in accordance with the Helsinki Convention and approved by the local Ethics Committee of Wrocław Medical University. Written informed consent to take part in the study was obtained from each person. Fifty-eight patients with Type 2 diabetes (28 women and 30 men), aged from 40 to 65 years old (mean age 57.6±8.5 years), were enrolled in the study. Duration of diabetes ranged from 1 to 27 years (mean 6.4±6.4 years). All patients received combined oral antidiabetic treatment

Results

The clinical characteristics of all study populations are presented in Table 1, Table 2. Briefly, diabetic patients weighed significantly more than the control group: higher BMI (P<.001), WHR (P<.001) values, mean systolic blood pressure (P<.001); fasting insulin concentration (P<.002), insulin-resistance index (P<.001), triglyceridemia (P<.006), and a reduction in HDL cholesterol concentration (P<.001). Noted differences in levels of uric acid (P<.005) and fibrinogen (P<.005) between groups

Discussion

Although previous publications have reported increased proinflammatory readiness in patients with diabetes (Cipolletta et al., 2005), it should be stressed that these studies focused mainly on serum immunological markers, such as serum IL-6 or TNFα concentrations (Cipolletta et al., 2005, Tuttle et al., 2004) and macrophage migration inhibitory factor (Herder et al., 2006), or cell-surface expression of receptors such as CD14, CD18, CCR2, CD40 (Burdon et al., 2006, Fogelstrand et al., 2004,

Conclusions

Atherogenesis is undoubtedly a multistage and multifactor process. Peripheral blood monocytes play a key role in both plaque formation and initiation. In this in vivo study, assuming that metabolic disorders are strong enough factors to induce monocyte activation, higher TNFα and IL-8 expression were detected. Restoring the balance between proinflammatory cytokine expression, such as TNFα and Il-8, and anti-inflammatory such as IL-10, in peripheral blood monocytes may prevent unfavorable local

Acknowledgments

This work was supported by a grant from the State Committee for Scientific Research No. 3 PO5B1232.

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