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10.1126/scitranslmed.aad9943

http://scihub22266oqcxt.onion/10.1126/scitranslmed.aad9943
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C5125295!5125295!27629486
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suck abstract from ncbi


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pmid27629486      Sci+Transl+Med 2016 ; 8 (356): 356ra119
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  • Enhanced T cell responses to IL-6 in type 1 diabetes are associated with early clinical disease and increased IL-6 receptor expression #MMPMID27629486
  • Hundhausen C; Roth A; Whalen E; Chen J; Schneider A; Long SA; Wei S; Rawlings R; Kinsman M; Evanko SP; Wight TN; Greenbaum CJ; Cerosaletti K; Buckner JH
  • Sci Transl Med 2016[Sep]; 8 (356): 356ra119 PMID27629486show ga
  • Interleukin-6 (IL-6) is a key pathogenic cytokine in multiple autoimmune diseases including rheumatoid arthritis and multiple sclerosis, suggesting that dysregulation of the IL-6 pathway may be a common feature of autoimmunity. The role of IL-6 in type 1 diabetes (T1D) is not well understood. We show that signal transducer and activator of transcription 3 (STAT3) and STAT1 responses to IL-6 are significantly enhanced in CD4 and CD8 T cells from individuals with T1D compared to healthy controls. The effect is IL-6-specific because it is not seen with IL-10 or IL-27 stimulation, two cytokines that signal via STAT3. An important determinant of enhanced IL-6 responsiveness in T1D is IL-6 receptor surface expression, which correlated with phospho-STAT3 levels. Further, reduced expression of the IL-6R sheddase ADAM17 in T cells from patients indicated a mechanistic link to enhanced IL-6 responses in T1D. IL-6-induced STAT3 phosphorylation was inversely correlated with time from diagnosis, suggesting that dysregulation of IL-6 signaling may be a marker of early disease. Finally, whole-transcriptome analysis of IL-6-stimulated CD4+ T cells from patients revealed previously unreported IL-6 targets involved in T cell migration and inflammation, including lymph node homing markers CCR7 and L-selectin. In summary, our study demonstrates enhanced T cell responses to IL-6 in T1D due, in part to, an increase in IL-6R surface expression. Dysregulated IL-6 responsiveness may contribute to diabetes through multiple mechanisms including altered T cell trafficking and indicates that individuals with T1D may benefit from IL-6-targeted therapeutic intervention such as the one that is being currently tested (NCT02293837).
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