A JAK1 Selective Kinase Inhibitor and Tofacitinib Affect Macrophage Activation and Function.
作者： L C S De Vries , J M Duarte , M De Krijger , O Welting , P H P Van Hamersveld
DOI: 10.1093/IBD/IZY364
关键词: Cytokine 、 Colitis 、 Pharmacology 、 Interferon 、 Janus kinase 、 Janus kinase inhibitor 、 Inflammatory bowel disease 、 Macrophage polarization 、 Tofacitinib 、 Medicine
摘要: Background Janus kinases (JAKs) mediate cytokine signaling involved in inflammatory bowel disease. The pan-JAK inhibitor tofacitinib has shown efficacy the treatment of ulcerative colitis. However, concerns regarding adverse events due to their wide spectrum inhibition fueled efforts develop selective JAK inhibitors. Given crucial role myeloid cells intestinal immune homeostasis, we evaluated effect and inhibitors on pro- anti-inflammatory macrophage polarization function (M1/M2) experimental Methods Murine bone marrow-derived macrophages or human monocytes were treated using JAK1 JAK3 (JAK1i;JAK3i) by transcriptional, functional, metabolic analyses. In vivo, oral administration JAK1i (10 30 mg/kg) was tested both acute rescue dextran sodium sulfate (DSS) Results Both but not JAK3i effectively inhibited STAT1 phosphorylation interferon gamma-induced transcripts M1 polarized macrophages. Strikingly, transcriptional profiling suggested a switch from M2 type macrophages, which supported increased protein expression M2-associated markers. addition, enhanced oxidative rates. did protect mice DSS-induced colitis ameliorated recovery weight loss disease activity during at highest dose. Conclusion induce phenotypical functional characteristics suggesting as main effector pathway for these cells. modestly affect
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