title: Hyporesponsiveness to the anti-inflammatory action of interleukin-10 in type 2 diabetes.
abstract: Chronic low-grade inflammation contributes to the pathology and complications of type 2 diabetes (T2D). Interleukin-10 (IL10), an anti-inflammatory cytokine, is suggested to play a protective role in T2D. However, the impact of T2D on IL10 function has not been previously assessed. We examined the ability of IL10 to inhibit inflammation in human T2D immune cells and explored underlying mechanisms using macrophage models. IL10 was less effective at inhibiting tumour necrosis factor (TNF)-α secretion in T2D whole blood cultures, which was not explained by altered IL10 receptor surface expression. These findings were observed in macrophages exposed to high glucose, which demonstrated similar IL10 resistance or hyporesponsiveness. These findings were also not explained by changes in IL10 receptor protein or other downstream signaling proteins. High glucose was also shown to impair the ability of IL10 to activate STAT3, a downstream signaling protein of IL10. Treatment with the SHIP1 agonist, AQX-MN100, reversed IL10 hyporesponsiveness in macrophages cultured in high glucose and showed equal effectiveness at different glucose conditions. This data supports the idea that IL10 hyporesponsiveness may contribute to chronic inflammation in T2D. These novel findings suggest that strategies aimed to overcome IL10 hyporesponsiveness may hold therapeutic potential for reducing inflammation in T2D.
authors.affiliation: School of Health and Exercise Sciences, University of British Columbia Okanagan, Kelowna, BC, Canada.
authors.forename: Julianne C
authors.initials: JC
authors.lastname: Barry
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, BC, Canada.|Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Soroush
authors.initials: S
authors.lastname: Shakibakho
authors.affiliation: School of Health and Exercise Sciences, University of British Columbia Okanagan, Kelowna, BC, Canada.
authors.forename: Cody
authors.initials: C
authors.lastname: Durrer
authors.affiliation: School of Health and Exercise Sciences, University of British Columbia Okanagan, Kelowna, BC, Canada.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Simtchouk
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, BC, Canada.|Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Kamaldeep K
authors.initials: KK
authors.lastname: Jawanda
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, BC, Canada.|Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Sylvia T
authors.initials: ST
authors.lastname: Cheung
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, BC, Canada.|Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Alice L
authors.initials: AL
authors.lastname: Mui
authors.affiliation: School of Health and Exercise Sciences, University of British Columbia Okanagan, Kelowna, BC, Canada.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Little
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D001786:Blood Glucose; D002460:Cell Line; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism; D016753:Interleukin-10 / Q000097:blood / Q000378:metabolism*; D053709:Interleukin-10 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / Q000378:metabolism; D011083:Polycyclic Compounds / Q000494:pharmacology; D012307:Risk Factors; D050796:STAT3 Transcription Factor / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: C544924:AQX MN100; D000893:Anti-Inflammatory Agents; D001786:Blood Glucose; D016207:Cytokines; D018836:Inflammation Mediators; D053709:Interleukin-10 Receptor alpha Subunit; D011083:Polycyclic Compounds; D050796:STAT3 Transcription Factor; D016753:Interleukin-10; C000606430:INPP5D protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases