326 Pancreatic beta-cell expression of IFN-gamma-Inducible Protein 10 (IP-10/CXCL10) in response to islet cell stress is required for early islet graft loss of function
Monday November 16, 2015 from 15:30 to 17:00
Plenary Room 1

Michael C. Lawrence, United States

Assistant Investigator

Islet Cell Laboratory

Baylor Research Institute


Pancreatic beta-cell expression of IFN-gamma-Inducible Protein 10 (IP-10/CXCL10) in response to islet cell stress is required for early islet graft loss of function

Mazhar Kanak2, Nofit Borenstein-Auerbach1, Charles Chang2, Rauf Shahbazov1, Gumpei Yoshimatsu1, Prathab Balaji1, Morihito Takita1, Marlon F Levy3, Bashoo Naziruddin3, Michael C Lawrence1.

1Islet Cell Laboratory, Baylor Research Institute, Dallas, TX, United States; 2Institute of Biomedical Studies, Baylor University, Waco, TX, United States; 3Annette C. and Harold C. Simmons Transplant Institutte, Baylor University Medical Center, Dallas, TX, United States

A major hurdle to improving the success of islet transplantation is the prevention of the inflammatory assault upon islets from which up to half of the graft is lost within the first few hours of transplantation. It is known that both autologous and allogeneic grafts undergo an immediate innate inflammatory reaction during the peritransplant period, however, the molecular events that initiate the response remain unclear. Islets have been observed to produce cytokines and chemokines in response to metabolic, inflammatory, and hypoxic stress that impair islet function. Here, we show that pancreatic beta cells produce the chemokine C-X-C motif ligand 10 or IFN-gamma-inducible protein 10 (CXCL10/IP-10) as a stress signaling response, which contributes to early islet graft loss of function. Inducible IP-10 gene expression was dependent on NFAT and NFkB signaling pathways which converged with ERK1/2, p38, and JNK MAP kinases to regulate IP-10 gene transcription. Inhibition of NFAT/NFkB or p38/JNK signaling resulted in promoter accumulation of HDAC3 upon the IP-10 gene promoter and blockade of IP-10 mRNA and protein expression. In contrast, HDAC1 was excluded from the insulin promoter. These inhibitory effects corresponded with enhanced insulin gene expression and islet function. Blockade of IP-10 signaling by a monoclonal anti-IP-10 antibody prevented IP-10 induced IP-10 production by islets. Transplanted islets from transgenic IP10-/- knockout donor mice into wild type mice recipients showed improved islet transplant outcomes. In contrast, IP10-/- knockout recipient mice showed no benefit when transplanted with wild type mouse donor islets. Overall, these data indicate that islet-derived IP-10 largely contributes to acute inflammatory destruction of islet grafts upon transplantation and blockade of IP-10 signaling may improve islet transplant outcomes. They also highlight the potential of 1) NFAT and NFkB, 2) p38 and JNK, and 3) HDAC1 and 3 as molecular targets in beta cells for inhibiting islet inflammation and enhancing islet survival and function.

Ana Rahman. Yoshiko Tamura. Baylor Health Care System. Baylor University Graduate Program.

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