Interleukin-10 resistance in type 2 diabetes is associated with defective STAT3 signaling in human blood leukocytes.

Abstract

Chronic inflammation is strongly implicated in the pathophysiology of type 2 diabetes (T2D), highlighting the need to better understand inflammatory processes in people living with T2D. Hyperglycemia blunts the anti-inflammatory actions of interleukin-10 (IL-10) - the most potent anti-inflammatory cytokine - but the mechanistic basis remains unclear. To test the hypothesis that signaling defects underpin this hyporesponsiveness to IL-10 action, fasted blood samples were obtained from individuals living with T2D (n=17, age: 64±9 yrs, HbA1c: 7.2±1.1%) and their age-matched counterparts without diabetes (n=19, 65±8 yrs, 5.5±0.3%). Blood leukocytes were analyzed for IL-10-mediated signaling, gene expression, and cytokine secretion using flow cytometry, qPCR, and whole-blood cultures, respectively. Despite no overt elevations in circulating pro- and anti-inflammatory cytokine concentrations, blood leukocytes from individuals with T2D exhibited exaggerated cytokine secretion when exposed to lipopolysaccharide (LPS) (p<0.05). IL-10's ability to activate its canonical transcription factor signal transducer and activator of transcription 3 (STAT3) was blunted in CD14 monocytes and CD4 lymphocytes from people with T2D (p<0.01) - a defect associated with lower IL-10 receptor expression on both cell types (p<0.05). This upstream signaling defect was accompanied by attenuated suppressor of cytokine signaling 3 (SOCS3) mRNA levels in IL-10 treated mononuclear cells (p=0.059) and higher lipopolysaccharide (LPS)-stimulated cytokine secretion from blood leukocytes exposed to IL-10 (p<0.01). Our findings identify defective IL-10-mediated signaling and gene expression as a potential mechanism underpinning IL-10 resistance in T2D, highlighting need for further investigation into therapeutic approaches targeting IL-10.