Global profiling of coxsackievirus- and cytokine-induced gene expression in human pancreatic islets.
OBJECTIVE
It is thought that enterovirus infections initiate or facilitate the pathogenetic processes leading to type 1 diabetes. Exposure of cultured human islets to cytolytic enterovirus strains kills beta cells after a protracted period, suggesting a role for secondary virus-induced factors such as cytokines.


METHODS
To clarify the molecular mechanisms involved in virus-induced beta cell destruction, we analysed the global pattern of gene expression in human islets. After 48 h, RNA was extracted from three independent human islet preparations infected with coxsackievirus B5 or exposed to interleukin 1beta (50 U/ml) plus interferon gamma (1,000 U/ml), and gene expression profiles were analysed using Affymetrix HG-U133A gene chips, which enable simultaneous analysis of 22,000 probe sets.


RESULTS
As many as 13,077 genes were detected in control human islets, and 945 and 1293 single genes were found to be modified by exposure to viral infection and the indicated cytokines, respectively. Four hundred and eighty-four genes were similarly modified by the cytokines and viral infection.


CONCLUSIONS
The large number of modified genes observed emphasises the complex responses of human islet cells to agents potentially involved in insulitis. Notably, both cytokines and viral infection significantly (p<0.02) increased the expression of several chemokines, the cytokine IL-15 and the intercellular adhesion molecule ICAM-1, which might contribute to the homing and activation of mononuclear cells in the islets during infection and/or an early autoimmune response. The present results provide novel insights into the molecular mechanisms involved in viral- and cytokine-induced human beta cell dysfunction and death.
Ylipaasto
P
P
Enterovirus Laboratory, Department of Viral Diseases and Immunology, National Public Health Institute, 00300 Helsinki, Finland.
Kutlu
B
B
Rasilainen
S
S
Rasschaert
J
J
Salmela
K
K
Teerijoki
H
H
Korsgren
O
O
Lahesmaa
R
R
Hovi
T
T
Eizirik
D L
DL
Otonkoski
T
T
Roivainen
M
M
D000368:Aged; D017951:Antigen Presentation / Q000235:genetics; D001324:Autoantigens / Q000276:immunology; D016923:Cell Death / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D003384:Coxsackievirus Infections / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000494:pharmacology*; D004260:DNA Repair / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007249:Inflammation / Q000235:genetics; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D008875:Middle Aged; D005810:Multigene Family; D009573:Nitrites / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051193:Toll-Like Receptors
D001324:Autoantigens; D016207:Cytokines; D008562:Membrane Glycoproteins; D009573:Nitrites; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors