Role of NF-kB in Release of Isletokines via Exosomes in Response to Islet Stress
1Department of Surgery, Virginia Commonwealth University, VCU Health, Richmond, VA, 2Islet Cell Lab, Baylor Scott and White Research Institute, Dallas, TX, 3Simmons Transplant Institute, Baylor Scott and White Medical Center, Dallas, TX
Meeting: 2019 American Transplant Congress
Abstract number: 371
Keywords: Apoptosis, Inflammation, Islets, Nuclear factor-kappa B (NF-kB)
Session Information
Session Name: Concurrent Session: Islet and Cell Transplantation
Session Type: Concurrent Session
Date: Monday, June 3, 2019
Session Time: 4:30pm-6:00pm
Presentation Time: 5:42pm-5:54pm
Location: Room 309
*Purpose: Human islets are exposed to a range of inflammatory stimuli upon transplantation that leads to poor graft survival. Identifying the various signaling events may provide strategies for intervention. Therefore, we studied the type of isletokines produced by islets and released via exosomes in response to stress
*Methods: Human islets were subjected to hypoxic and inflammatory conditions in vitro. Exosomes were isolated from the medium and characterized by TEM and surface marker expression analysis. Luminex multiplex assays were performed to identify isletokines released via islet exosomes. Western blot analysis was performed to identify the activation of signaling pathways in islets in response to hypoxia and cytokines. Withaferin A (WA) a plant derived compound known to block Nuclear Factor Kappa B was used to prevent isletokine release via islet exosomes, and effects of WA on other stress-signaling components was determined
*Results: Human islets exposed to hypoxia and proinflammatory cytokines showed significant activation of ER stress sensors IRE1α/XBP1/CHOP and also NF-κB signaling pathways resulting in release of exosomes containing IL-6, IL-8, MCP-1, and CXCL10. Prolonged release of exosomes containing isletokines induce significant c-Casp-3/Casp-3 mediated apoptosis in human islets. Pretreatment of islets with WA significantly suppressed the activation of canonical NF-κB RelA/p65, ER stress signaling, and also prevented release of isletokines in the exosomes in response to hypoxic and pro-inflammatory stimulation. Furthermore, we identified other stress signaling components in islets included AKT/mTOR/GSK3B, which were activated in response to hypoxia and proinflammatory cytokines and blocked by WA except for GSK3b
*Conclusions: Human islets exposed to pro-inflammatory and hypoxic stress release exosomes carrying inflammatory isletokines. Inhibition of NFkB p65 with WA significantly suppressed isletokine release via exosomes and also the activation of AKT/mTOR/IRE1α. These findings indicate that stress-induced signaling can be targeted to prevent early innate immune destruction of islets during transplantation
To cite this abstract in AMA style:
Saravanan P, Kanak M, Kalivarathan J, Lawrence M, Levy M, Naziruddin B. Role of NF-kB in Release of Isletokines via Exosomes in Response to Islet Stress [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/role-of-nf-kb-in-release-of-isletokines-via-exosomes-in-response-to-islet-stress/. Accessed May 12, 2025.« Back to 2019 American Transplant Congress