Human islets express a marked proinflammatory molecular signature prior to transplantation.

Cell Transplant 2012 8;21(9):2063-78. Epub 2012 Mar 8.

Peter Wills Bioinformatics Centre, Darlinghurst, Australia.

In the context of islet transplantation, experimental models show that induction of islet intrinsic NF-κB-dependent proinflammatory genes can contribute to islet graft rejection. Isolation of human islets triggers activation of the NF-κB and mitogen-activated kinase (MAPK) stress response pathways. However, the downstream NF-κB target genes induced in human islets during the isolation process are poorly described. Therefore, in this study, using microarray, bioinformatic, and RTqPCR approaches, we determined the pattern of genes expressed by a set of 14 human islet preparations. We found that isolated human islets express a panel of genes reminiscent of cells undergoing a marked NF-κB-dependent proinflammatory response. Expressed genes included matrix metallopeptidase 1 (MMP1) and fibronectin 1 (FN1), factors involved in tissue remodeling, adhesion, and cell migration; inflammatory cytokines IL-1β and IL-8; genes regulating cell survival including A20 and ATF3; and notably high expression of a set of chemokines that would favor neutrophil and monocyte recruitment including CXCL2, CCL2, CXCL12, CXCL1, CXCL6, and CCL28. Of note, the inflammatory profile of isolated human islets was maintained after transplantation into RAG(-/-) recipients. Thus, human islets can provide a reservoir of NF-κB-dependent inflammatory factors that have the potential to contribute to the anti-islet-graft immune response. To test this hypothesis, we extracted rodent islets under optimal conditions, forced activation of NF-κB, and transplanted them into allogenic recipients. These NF-κB activated islets not only expressed the same chemokine profile observed in human islets but also struggled to maintain normoglycemia posttransplantation. Further, NF-κB-activated islets were rejected with a faster tempo as compared to non-NF-κB-activated rodent islets. Thus, isolated human islets can make cell autonomous contributions to the ensuing allograft response by elaborating inflammatory factors that contribute to their own demise. These data highlight the potential importance of islet intrinsic proinflammatory responses as targets for therapeutic intervention.

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http://dx.doi.org/10.3727/096368911X627372DOI Listing
December 2013
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References

(Supplied by CrossRef)

Abdelli S. et al.
Diabetes 2004

Arnush M. et al.
J. Clin. Invest. 1998

Avlonitis V. S. et al.
Am. J. Transplant. 2005

Beg A. A. et al.
Science 1996

Bennet W. et al.
Diabetes 1999

Bertuzzi F. et al.
J. Clin. Endocrinol. Metab. 2004

Bottino R. et al.
Diabetes 2002

Bottino R. et al.
Diabetes 2004

Bottino R. et al.
Diabetes 1998

Darville M. I. et al.
Diabetes 2001

Emamaullee J. A. et al.
Diabetes 2007

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