In the present study, we confirmed that young adolescents who are overweight and obese had decreased circulating IL10 concentration and increased pro-inflammatory cytokines TNFα, IL1β and NO. Our study also found that pro-inflammatory cytokine IL1β and IL10 are independently associated. A decline in serum IL10 concentration in overweight and obese adolescents may further contribute to the IL1β-mediated inflammatory environment associated with obesity. IL1β has been associated with the destruction of the insulin-producing beta cell [28
]. Administration of neutralizing monoclonal antibodies to IL1β improved glycemic control and beta cell function in type 2 diabetic patients [29
]. Our study showed IL10 concentration was neither correlated with blood glucose homeostasis variables nor blood lipid profiles. This is partially explained by the low prevalence rate of MetS in the study subjects. IL10 plays a critical role in limiting inflammation and a switch in anti- and pro-inflammatory balance towards pro-inflammatory state in overweight and obese adolescents may promote the progression of normal glucose tolerance to insulin resistance in adulthood [30
]. The pathogenesis of type 2 diabetes is complex, involving the interaction of genetic and environmental risk factors. Therefore, a longitudinal follow up study on obese children and adolescents is needed to clarify the role of IL10 in the progression of type 2 diabetes and MetS.
The association between IL10 and IL1β was more pronounced in girls who are overweight or obese. Both overweight/obese boys and girls had elevated serum IL1β concentrations. However, correlations between IL10 and IL1β concentrations were greater in overweight/obese girls (R2
=0.212) than boys (R2
=0.049). Corcoran et al.
investigated the effect of estrogen and testosterone on the expression of pro-inflammatory mediators in macrophages obtained from patients with coronary heart disease [31
]. The authors showed testosterone reduced the expression of TNFα and IL1β; by contrast, estrogen did not have these adverse effects [31
]. In our study, serum IL1β concentrations were similarly increased in both overweight/obese boys and girls. This suggests that the difference between the two groups is less likely to be explained by the effect of sex hormones on IL1β. Adipose tissues derived adiponectin is a potential mediator of IL10 [32
]. Adiponectin concentrations are inversely correlated with waist circumference, BMI and total body fat [33
]. We found that overweight/obese boys had slightly higher waist circumference than overweight/obese girls (84.7±3.2 cm v.s. 81.1±2.7 cm; p=0.06). Although it did not reach statistical significance, overweight/obese boys had slightly lower IL10 concentrations when compared with overweight/obese girls. This contributed to a lower ratio of IL10/ IL1β in overweight/obese boys than girls (8.77±0.65 v.s. 9.93±0.86; p=0.35). We hypothesize that adiponectin concentrations may contribute to the gender difference in IL10 and IL1β association in overweight/obese adolescents.
Interleukins (ILs) are key mediators of the innate immune response and inflammatory process. So far, 11 members of the IL1 family have been identified including IL1α, IL1β and IL1 receptor antagonist (IL1Ra) [28
]. Circulating IL1β and IL1Ra are elevated in patients with obesity and type 2 diabetes [34
]. Short-term IL1α treatment transiently causes insulin resistance at insulin receptor substrate 1 level in 3T3L1 adipocytes [35
]. IL1Ra is regarded as anti-inflammatory cytokine but it does not directly elicit an anti-inflammatory response. It binds tightly to IL1α and IL1β receptor on the cell surface, hence blocking the activity of either IL1α or IL1β. A recent report showed 13 weeks of IL1Ra therapy improved glycemic control and the function of the insulin-producing beta cell in patients with type 2 diabetes [34
In this study, we also observed a positive relationship between IL10 and iron status. Associations between obesity and poor iron status have recently been described in White and Hispanic children [36
]. However, we found no difference in iron status between normal body weight and overweight/obese adolescents (data not shown). The relationship between IL10 and iron metabolism is poorly understood. Patients with Crohn’s disease receiving higher doses of IL10 developed anemia and a dose-dependent increase of serum ferritin concentration [19
]. The authors suggested that hyperferritinemia may result from direct stimulation of ferritin translation by IL10 via the suppression of the binding affinity of iron regulatory proteins to the 5’-untranslated region of ferritin mRNA in human monocytic cells [19
]. Macrophages play a key role in the iron homeostasis. Through erythrophagocytosis of senescent red blood cells, macrophages recycle and redistribute heme iron to the plasma. Chau et al.
showed IL10 triggers expression of heme oxygenase 1 (HO-1) via the p38 MAPK pathway and IL10-HO1 pathways are critical for the protection against LPS-induced septic shock in mice [38
]. These data suggest that abnormal high concentration of IL10 may limit iron bioavailability to erythroid progenitor cells; whilst, defective IL10 production may impair HO1 mediated anti-inflammatory and anti-oxidant responses. Nevertheless, the consequences of defective IL10 synthesis and erythrogenesis in overweight and obese adolescents need to be further investigated in a longitudinal study.
There are several limitations in our study. The cross-sectional nature of the current study and the relative small sample size are one of the limitations. Further, the inverse correlation between serum IL10 and pro-inflammatory cytokines may be casual and related to IL10 polymorphisms. IL-10 secretion is tightly controlled and under a stringent genetic regulation with 75% of heritability [39
]. The three polymorphisms -1082G/A, -819C/T, and -592C/A in the IL10 promoter region were reported to influence IL10 transcription. A promoter polymorphism (−592C/A) was associated with lower circulating IL-10 levels and an increased risk for obesity and insulin resistance in Italian people [40
]. However, this association was not confirmed in the Chinese population [41
]. Another limitation is that we could not confirm which IL10-producing cells are affected in obese children.