Resistin Inhibits Essential Functions of Polymorphonuclear Leukocytes

Abstract

The serum levels of resistin, a 12-kDa protein primarily expressed in inflammatory cells in humans, are increased in patients with chronic kidney disease and in those with diabetes mellitus. Both groups of patients have an increased risk of infections mainly as a result of disturbed polymorphonuclear leukocyte (PMNL) functions. Therefore, we investigated the influence of resistin on human PMNLs. Serum resistin concentrations were determined with a sandwich enzyme immunoassay. Using PMNLs from healthy subjects, chemotaxis was tested by the under-agarose method. Flow cytometric assays to measure oxidative burst and phagocytosis were conducted in whole blood. The uptake of deoxyglucose was determined as measure of the PMNL activation state. The activity of intracellular kinases was assessed by Western blotting and by in vitro kinase assays. Resistin inhibited PMNL chemotaxis and decreased the oxidative burst stimulated by Escherichia coli and by PMA, but did not influence PMNL phagocytosis of opsonized E. coli and PMNL glucose uptake. The inhibition of PMNLs by resistin was observed at concentrations found in serum samples of uremic patients, but not in concentrations measured in healthy subjects. Experiments with specific signal transduction inhibitors and measurements of intracellular kinases suggest that PI3K is a major target of resistin. In conclusion, resistin interferes with the chemotactic movement and the stimulation of the oxidative burst of PMNL, and therefore may contribute to the disturbed immune response in patients with increased resistin serum levels such as uremic and diabetic subjects.

Neutrophil-Derived Hyperresistinemia in Severe Acute Streptococcal Infections

“…As previously mentioned, resistin has been ascribed numerous proinflammatory properties in humans, whereas its role in glucose metabolism and homeostasis remains controversial. Furthermore, two recent reports described immunosuppressive effects of resistin on immune cells, including interference with chemotactic and oxidative responses of neutrophils (29), as well as suppression of Ag uptake and presentation by dendritic cells (30). Yet another level of complexity is added by the fact that resistin has a tendency to form oligomers both in vitro and in vivo (31)(32)(33).…”

Increased resistin may suppress reactive oxygen species production and inflammasome activation in type 2 diabetic patients with pulmonary tuberculosis infection

“…Previous studies have showed the anti-oxidant effect of resistin on neutrophils through PI3K signaling pathway [10]. We hence went on to examine whether resistin can directly inhibit the ROS production by macrophages.…”

“…Serum resistin level hence has been used as an inflammatory biomarker in various diseases including sepsis, rheumatoid arthritis, and atherosclerosis [7e9]. Furthermore, resistin was recently reported to impair the chemotaxis and production of reactive oxygen species (ROS) in neutrophils [10].…”

The role of resistin as a regulator of inflammation: Implications for various human pathologies

“…Resistin was also correlated with TNF-α, suggesting that it have a role in the sub-clinical inflammatory state of chronic kidney disease [54]. Resistin may also interfere with the chemotactic ability and oxidative burst of polymorphonuclear 18 leukocytes and might contribute to the disturbed immune response in conditions with increased serum resistin levels, such as uremia [129].…”