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

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 ( = 17, age: 64 ± 9 yr, HbA1c: 7.2 ± 1.1%) and their age-matched counterparts without diabetes ( = 19, 65 ± 8 yr, 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) ( < 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 ( < 0.01)-a defect associated with lower IL-10 receptor expression on both cell types ( < 0.05). This upstream signaling defect was accompanied by attenuated suppressor of cytokine signaling 3 mRNA levels in IL-10-treated mononuclear cells ( = 0.059) and higher lipopolysaccharide (LPS)-stimulated cytokine secretion from blood leukocytes exposed to IL-10 ( < 0.01). Our findings identify defective IL-10-mediated signaling and gene expression as a potential mechanism underpinning IL-10 resistance in T2D, highlighting the need for further investigation into therapeutic approaches targeting IL-10. Our findings demonstrate that immune cells from people with type 2 diabetes (T2D) are less responsive to the anti-inflammatory actions of interleukin-10 (IL-10), which may drive chronic inflammation in this population. We identify T2D-associated defects at multiple steps of the IL-10 cascade-including IL-10 receptor expression, STAT3 signaling, SOCS3 mRNA, and cytokine secretion. Our findings highlight defective IL-10 action as a potential therapeutic target to ameliorate inflammation in T2D.