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Increased circulating interleukin (IL)-10 is reported in patients with acute myocardial infarction (AMI)1 and in mice with myocardial ischaemia/reperfusion2; induction of IL-10 mRNA in ischaemic/reperfused myocardium3 was also recently reported. Ischaemic/reperfused myocardium is protected by IL-10 through inhibition of tumour necrosis factor α production2 and down regulation of IL-6 mRNA in a canine model.3 We have already shown induction of circulating IL-6, and a positive relation between natriuretic peptides in AMI.4 We also showed IL-6 expression in ischaemic myocardium5; however, no study has investigated circulating concentrations of IL-6 and IL-10 at the same time. Increased IL-10 inhibited IL-12 induction in an animal model,3 while circulating IL-12 has not been investigated in patients with AMI. In this study we show a reciprocal increase in circulating IL-10 and IL-6, but not IL-12, in patients with AMI.
Twenty patients admitted to Fujioka Hospital within six hours of the onset of AMI symptoms, and 20 healthy controls, were enrolled after informed consent was obtained. In patients with AMI, informed consent was obtained at admission; all patients immediately underwent percutaneous transluminal coronary angioplasty (PTCA). The 20 patients comprised 16 men and 4 women aged 45–69 years, and the 20 controls were 16 men and 4 women aged 45–65 years. No subjects had collagen diseases, liver disease, renal failure, malignancy, infection, autoimmune disease, or thyroid disease. The diagnosis of AMI was based on chest pain resistant to glyceryl trinitrate, electrocardiographic ST segment elevations in more than two leads with or without Q wave formation, and significant increases in plasma creatine phosphokinase (CK) and lactate dehydrogenase (LDH). The MB isoenzyme of CK, a relatively specific indicator of myocardial damage, was elevated by > 5% in all 20 patients. Blood specimens were drawn from the femoral vein on admission and every 12 hours until 120 hours after admission. Plasma was centrifuged for 15 minutes at 3000 rpm at 4ºC and stored at −80ºC until assayed. IL-6 was measured with a chemiluminescent enzyme immunoassay kit (Fujirebio, Tokyo, Japan). IL-10 and IL-12 were measured by another chemiluminescent enzyme immunoassay kit (BioSource International Inc, Camarillo, California, USA). CK and LDH were measured by autoanalyser. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were measured by radioimmunoassay. Data are presented as mean (SD). Statistical analysis was performed using unpaired t test, analysis of variance (ANOVA), or linear regression. A probability level of p < 0.05 was considered significant.
Mean (SD) concentrations of IL-6, IL-10, and IL-12 in controls were 0.7 (0.5), 3.4 (1.3), and 53.9 (16.1) pg/ml, respectively, and in patients with AMI were 18.5 (8.5), 14.9 (6.2), and 55.3 (14.9) pg/ml, respectively. Mean concentrations of plasma IL-6 and IL-10 were significantly increased in patients with AMI compared with controls, and IL-10 reached a peak concentration within 24 hours after onset of chest pain (fig 1A). A prolonged increase in IL-6 concentration was detected, showing two peaks after IL-10 decreased (fig 1B). Circulating IL-12 did not differ from controls throughout the study (fig 1C). Peak concentrations of IL-10 were positively correlated with both ANP and BNP (p < 0.01, R 2 = 0.41; p < 0.01, R 2 = 0.36, respectively, data not shown). The first peak of IL-6 in AMI was correlated with ANP and BNP as previously reported (data not shown).4 Mean concentrations of IL-10 were significantly higher in the 11 patients with severe AMI (16.8 (6.8) pg/ml, Killip class II, III, or IV, group B) than in the nine patients with uncomplicated AMI (7.4 (3.3) pg/ml, Killip class I, group A). Neither IL-10 nor IL-12 correlated with CK or LDH, while IL-6 positively correlated with CK and LDH (data not shown). No significant relation was detected between IL-6 and IL-10, between IL-6 and IL-12, and between IL-10 and IL-12 in patients with AMI.
In this study we have shown reciprocal elevation of IL-10 and IL-6 in patients with AMI. A recent study showed that IL-10 induction and down regulation of IL-6 in myocardium required reperfusion after ischaemia, while ischaemia without reperfusion induced prolonged IL-6 mRNA expression.3 In our subjects both IL-10 and IL-6 were already increased at admission and IL-6 showed two peaks after IL-10 subsidence. All 20 patients received PTCA treatment within 12 hours after onset of chest pain; however complete reperfusion was not possible. Mean concentrations of IL-10 were significantly higher in the 11 patients with severe AMI (Killip class II, III, or IV) than in the nine patients with uncomplicated AMI (Killip I). These results were consistent with a previous report.1 We have also shown that IL-10 was positively associated with ANP and BNP, as well as IL-6.4 These findings suggest that IL-10 is a marker of myocardial damage or reperfused myocardium in AMI.
In patients with AMI plasma IL-12 concentration was the same as in normal controls, in agreement with a canine model,3 and no IL-12 elevation was detected after IL-10 decrease. No correlation between IL-10 and IL-12 was identified.
In conclusion, our study shows reciprocal elevation of circulating IL-10 and IL-6 following AMI. Further study is required to reveal the physiological role of IL-10 in patients with AMI.