Interleukin-37 treatment of mice with metabolic syndrome improves insulin sensitivity and reduces pro-inflammatory cytokine production in adipose tissue

Abstract

Obesity and the metabolic syndrome are characterized by chronic, low-grade inflammation mainly originating from expanding adipose tissue and resulting in inhibition of insulin signaling and disruption of glycemic control. Transgenic mice expressing human interleukin 37 (IL-37), an anti-inflammatory cytokine of the IL-1 family, are protected against metabolic syndrome when fed a high-fat diet (HFD) containing 45% fat. Here, we examined whether treatment with recombinant IL-37 ameliorates established insulin resistance and obesity-induced inflammation. Wildtype mice were fed a HFD for 22 weeks and then treated daily with IL-37 (1 µg/mouse) during the last 2 weeks. Compared with vehicle only-treated mice, IL-37-treated mice exhibited reduced insulin in the plasma and had significant improvements in glucose tolerance, and insulin content of the islets. The IL-37 treatment also increased the levels of circulating IL-1 receptor antagonist. Cultured adipose tissues revealed that IL-37 treatment significantly decreases spontaneous secretions of IL-1β, tumor necrosis factor α (TNFα), and C-X-C motif chemokine ligand 1 (CXCL-1). We also fed mice a 60% fat diet with concomitant daily IL-37 for 2 weeks and observed decreased secretion of IL-1β, TNFα, and IL-6 and reduced intracellular levels of IL-1α in the liver and adipose tissue, along with improved plasma glucose clearance. Compared with vehicle treatment, these IL-37-treated mice had no apparent weight gain. In human adipose tissue cultures, the presence of 50 pM IL-37 reduced spontaneous release of TNFα and 50% of lipopolysaccharide-induced TNFα. These findings indicate that IL-37's antiinflammatory effects can ameliorate established metabolic disturbances during obesity.

Short‐term interleukin‐37 treatment improves vascular endothelial function, endurance exercise capacity, and whole‐body glucose metabolism in old mice

“…Data are summarized in Supplemental Figure . Consistent with our previous work, concentrations of IL‐6 in plasma ( p = .09), aorta lysates ( p < .05), and quadriceps lysates ( p = .10) were or tended to be higher in recIL‐37‐ vs. vehicle‐treated mice (Cavalli et al, ), and concentrations of anti‐inflammatory IL‐1 receptor antagonist (IL‐1Ra) tended to be higher in plasma ( p = .09) in recIL‐37‐ vs. vehicle‐treated mice (Ballak et al, ). Concentrations of KC (murine chemokine ligand 1, CXCL1) were higher in plasma of recIL‐37 animals ( p < .05).…”

“…Following in vivo baseline testing, old mice received daily IP injections of 1 μg recIL‐37 ( N = 15) in 200 μl PBS or vehicle (200 μl PBS; N = 17) for 10–14 days (Ballak et al, ). The recombinant human IL‐37 that was used in these experiments was expressed in E. coli with an N terminus at valine 46 and C terminus at residues 218 and purified to homogeneity, as reported previously (Li et al, ).…”

“…Administration of IL‐37 suppresses inflammation in pro‐inflammatory states and disorders, while reducing morbidity (Ballak et al, ; Moretti et al, ; Nold et al, ; Teng et al, ). We recently reported that treatment with recombinant IL‐37 (recIL‐37) improved endurance exercise tolerance in young mice during lipopolysaccharide‐induced inflammation (Cavalli et al, ) and improved glucose metabolism in young mice with high‐fat feeding‐induced obesity and inflammation (Ballak et al, ). IL‐37 treatment also improved exercise performance in healthy (young) control mice without experimentally induced inflammation.…”

Current perspectives on the interleukin‐1 family as targets for inflammatory disease

“…Together these observations raise significant implications for the possibility of harnessing IL‐37 activity to treat inflammatory disease in humans. In this regard it is particularly noteworthy that administration of recombinant IL‐37 has also proven effective in treating preclinical models of inflammatory diseases including obesity dependent metabolic disease, asthma, endotoxaemia and rheumatoid arthritis . Such observations hold considerable promise for the future translation of these effects to patients.…”

Immunometabolism in type 2 diabetes mellitus: tissue-specific interactions

“…Moreover, HFD-fed mice treated with recombinant IL-37 displayed improved insulin sensitivity and obesity-induced inflammation [102].…”