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Soluble interleukin-13r?1: a circulating regulator of glucose.

ABSTRACT: Soluble IL-13 receptor-?1, or sIL13r?1, is a soluble protein that binds to interleukin-13 (IL-13) that has been previously described in mice. The function of sIL13r?1 remains unclear, but it has been hypothesized to act as a decoy receptor for IL-13. Recent studies have identified a role for IL-13 in glucose metabolism, suggesting that a decoy receptor for IL-13 might increase circulating glucose levels. Here, we report that delivery of sIL13r?1 to mice by either gene transfer or recombinant protein decreases blood glucose levels. Surprisingly, the glucose-lowering effect of sIL13r?1 was preserved in mice lacking IL-13, demonstrating that IL-13 was not required for the effect. In contrast, deletion of IL-4 in mice eliminated the hypoglycemic effect of sIL13r?1. In humans, endogenous blood levels of IL13r?1 varied substantially, although there were no differences between diabetic and nondiabetic patients. There was no circadian variation of sIL13r?1 in normal human volunteers. Delivery of sIL13r?1 fused to a fragment crystallizable (Fc) domain provided sustained glucose lowering in mice on a high-fat diet, suggesting a potential therapeutic strategy. These data reveal sIL13r?1 as a circulating human protein with an unexpected role in glucose metabolism.

SUBMITTER: Rachmin I

PROVIDER: S-EPMC5814599 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Soluble interleukin-13rα1: a circulating regulator of glucose.

Rachmin Inbal I O'Meara Caitlin C CC Ricci-Blair Elisabeth M EM Feng Yilin Y Christensen Emily M EM Duffy Jeanne F JF Zitting Kirsi M KM Czeisler Charles A CA Pancoast James R JR Cannon Christopher P CP O'Donoghue Michelle L ML Morrow David A DA Lee Richard T RT

American journal of physiology. Endocrinology and metabolism 20170905 6

Soluble IL-13 receptor-α1, or sIL13rα1, is a soluble protein that binds to interleukin-13 (IL-13) that has been previously described in mice. The function of sIL13rα1 remains unclear, but it has been hypothesized to act as a decoy receptor for IL-13. Recent studies have identified a role for IL-13 in glucose metabolism, suggesting that a decoy receptor for IL-13 might increase circulating glucose levels. Here, we report that delivery of sIL13rα1 to mice by either gene transfer or recombinant pro ...[more]

PMID: 28874358

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Project description:BackgroundThe soluble interleukin-2 receptor (sIL-2R, sIL2R, sTAC, sCD25) is a reliable biomarker for disease activity in inflammatory disorders such as sarcoidosis. Based on the essential pathogenic role of inflammation for progression of liver diseases, we hypothesized that sIL-2R might be an indicator of inflammatory cell activation and disease severity in patients with chronic liver diseases (CLD).MethodsWe measured sIL-2R serum levels in 71 patients with different stages and etiologies of CLD in comparison to 41 healthy controls. Serum sIL-2R concentrations were correlated with laboratory markers of liver diseases, cytokine / chemokine levels and circulating immune cell subpopulations as simultaneously assessed by FACS analysis from peripheral leukocytes.ResultsCLD patients showed significantly elevated serum sIL-2R levels compared with controls. sIL-2R was significantly higher in patients with compared to patients without established liver cirrhosis and increased with the Child-Pugh stage of cirrhosis, independent of the underlying etiology. sIL-2R levels correlated inversely with parameters indicating the hepatic biosynthetic capacity, such as albumin or international normalized ratio, and positively with non-invasive markers of liver fibrosis such as hyaluronic acid or procollagen-III-peptide. Circulating immune cells might represent a major source of sIL-2R. In fact, sIL2-R levels correlated closely with circulating monocytes, especially non-classical CD14+ CD16+ monocytes, which were found to express high levels of CD25 by FACS. Pro-inflammatory cytokines, including IL-2, IFNγ or IL-6, and chemokines were also associated with sIL2-R. In addition, renal failure was an important confounder of sIL-2R levels independent of liver dysfunction and inflammation.ConclusionssIL-2R is elevated in patients with liver diseases and cirrhosis, is associated with circulating inflammatory cells and is increased in concomitant renal failure. These data indicate that sIL-2R might be a potential marker for immune cell activation in CLD, especially for proinflammatory and profibrogenic non-classical CD14 + CD16+ monocytes.

Project description:BACKGROUND:Previously, we have demonstrated that Interleukin 13 receptor alpha 2 (IL-13R?2) is overexpressed in approximate 78% Glioblastoma multiforme (GBM) samples. We have also demonstrated that IL-13R?2 can serve as a target for cancer immunotherapy in several pre-clinical and clinical studies. However, the significance of overexpression of IL-13R?2 in GBM and astrocytoma and signaling through these receptors is not known. IL-13 can signal through IL-13R via JAK/STAT and AP-1 pathways in certain cell lines including some tumor cell lines. Herein, we have investigated a role of IL-13/IL-13R?2 axis in signaling through AP-1 transcription factors in human glioma samples in situ. METHODS:We examined the activation of AP-1 family of transcription factors (c-Jun, Fra-1, Jun-D, c-Fos, and Jun-B) after treating U251, A172 (IL-13R?2 +ve) and T98G (IL-13R?2 -ve) glioma cell lines with IL-13 by RT-qPCR, and immunocytochemistry (ICC). We also performed colorimetric ELISA based assay to determine AP-1 transcription factor activation in glioma cell lines. Furthermore, we examined the expression of AP-1 transcription factors in situ in GBM and astrocytoma specimens by multiplex-immunohistochemistry (IHC). Student t test and ANOVA were used for statistical analysis of the results. RESULTS:We have demonstrated up-regulation of two AP-1 transcription factors (c-Jun and Fra-1) at mRNA and protein levels upon treatment with IL-13 in IL-13R?2 positive but not in IL-13R?2 negative glioma cell lines. Both transcription factors were also overexpressed in patient derived GBM specimens, however, in contrast to GBM cell lines, c-Fos is also overexpressed in patient derived specimens. Astrocytoma specimens showed lesser extent of immunostaining for IL-13R?2 and three AP-1 factors compared to GBM specimens. By transcription factor activation assay, we demonstrated that AP-1 transcription factors (C-Jun and Fra-1) were activated upon treatment of IL-13R?2?+?GBM cell lines but not IL-13R?2?-?GBM cell line with IL-13. Our results demonstrate functional activity of AP-1 transcription factor in GBM cell lines in response to IL-13. CONCLUSIONS:These results indicate that IL-13/IL-13R?2 axis can mediate signal transduction in situ via AP-1 pathway in GBM and astrocytoma and may serve as a new target for GBM immunotherapy.

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Soluble interleukin-13r?1: a circulating regulator of glucose.

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Soluble interleukin-13rα1: a circulating regulator of glucose.

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