IL-1beta and IFN-gamma induce the expression of diverse chemokines and IL-15 in human and rat pancreatic islet cells, and in islets from pre-diabetic NOD mice.
OBJECTIVE
Cytokines and chemokines are important mediators of immune responses due to their ability to recruit and activate leukocytes. Using microarray analysis we observed that rat beta cells exposed to IL-1beta and IFN-gamma have increased mRNA levels of chemokines and IL-15. The aim of this study was to characterize the expression of IP-10, MIP-3alpha, fractalkine and IL-15 in rat beta cells, human pancreatic islets, and in islets isolated from NOD mice, both during the pre-diabetic period and following islet transplantation.


METHODS
FACS-purified rat beta cells and human islets were cultured with IL-1beta, IFN-gamma and/or TNF-alpha. Islets were isolated from NOD or BALB/c mice at different ages. For syngeneic islet transplantation, 2- or 3-week-old NOD islets were grafted under the kidney capsule of spontaneously diabetic NOD recipients. Chemokine and IL-15 mRNA expression and protein release were evaluated, respectively, by RT-PCR and ELISA.


RESULTS
Human islets and rat beta cells express IP-10, MIP-3alpha, fractalkine and IL-15 mRNAs upon exposure to cytokines. The expression of IL-15, IP-10 and fractalkine is regulated by IFN-gamma, while the expression of MIP-3alpha is IL-1beta-dependent. Moreover, cytokines induced IL-15, IP-10, Mig, I-TAC and MIP-3alpha protein accumulation in culture medium from human islets. In vivo, there was an age-related increase in IL-15, IP-10 and MIP-3alpha expression in islets isolated from NOD mice. Following syngeneic islet transplantation, increased expression of IL-1beta, IFN-gamma, fractalkine, IP-10, MCP-1 and MIP-3alpha mRNAs were observed in the grafts.


CONCLUSIONS
Cytokine-exposed islets or beta cells express chemokines and IL-15. This could contribute to the recruitment and activation of mononuclear cells and development of insulitis in early Type 1 diabetes and during graft destruction.
Cardozo
A K
AK
Laboratory of Experimental Medicine, Université Libre de Bruxelles, Route de Lennik 808, CP 618, 1070 Brussels, Belgium.
Proost
P
P
Gysemans
C
C
Chen
M-C
MC
Mathieu
C
C
Eizirik
D L
DL
D000328:Adult; D000818:Animals; D054418:Chemokine CCL20; D054428:Chemokine CX3CL1; D054357:Chemokine CXCL10; D018925:Chemokines / Q000378:metabolism*; D019742:Chemokines, CC / Q000235:genetics; D020523:Chemokines, CX3C / Q000235:genetics; D019743:Chemokines, CXC / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology*; D019409:Interleukin-15 / Q000235:genetics / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism*; D019402:Macrophage Inflammatory Proteins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
C108355:CCL20 protein, human; C515538:CX3CL1 protein, human; D054418:Chemokine CCL20; D054428:Chemokine CX3CL1; D054357:Chemokine CXCL10; D018925:Chemokines; D019742:Chemokines, CC; D020523:Chemokines, CX3C; D019743:Chemokines, CXC; C515539:Cx3cl1 protein, mouse; C515540:Cx3cl1 protein, rat; D007375:Interleukin-1; D019409:Interleukin-15; D019402:Macrophage Inflammatory Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D007371:Interferon-gamma