Pre-conditioning with synthetic CpG-oligonucleotides attenuates myocardial ischemia/reperfusion injury via IL-10 up-regulation.
The aim of the study was to investigate whether pre-conditioning with CpG-oligodeoxynucleotides (CpG-ODN) may change cardiac ischemia/reperfusion (I/R)-dependent inflammation and modulates infarct size and cardiac performance. WT and TLR9-deficient mice were pre-treated with 1668-, 1612- and H154-thioate or D-Gal as control. Priming with 1668-thioate significantly induced inflammatory mediators in the serum and a concomitant increase of immune cells in the blood and spleen of WT mice. Furthermore, it induced myocardial pattern recognition receptors and pro-inflammatory cytokines peaking 2 h after priming and a continuous increase of IL-10. 16 h after pre-conditioning, myocardial ischemia was induced for 1 h. Infarct size determined after 24 h of I/R was reduced by 75 % due to pre-conditioning with 1668-thioate but not in the other groups. During reperfusion, cytokine expression in 1668-thioate primed mice increased further with IL-10 exceeding the other mediators by far. These changes were observed neither in animals pre-treated with 1612- or H154-thioate nor in TLR9-deficient mice. The 1668-thioate-dependent increase of IL-10 was further supported by results of a micro-array analysis 3 h after begin of reperfusion. Block of IL-10 signaling increased I/R size and prevented influence of priming. In the group pre-treated with 1668-thioate, cardiac function was preserved 24 h, 14 days and 28 days after I/R, whereas animals without pre-conditioning exhibited impaired heart function 24 h and 14 days after I/R. The excessive 1668-thioate-dependent IL-10 up-regulation during pre-conditioning and after I/R seems to be the key factor for reducing infarct size and improving cardiac function. This is in agreement with the finding that IL-10 block prevents cardioprotection by pre-conditioning.
Department of Anaesthesiology and Intensive Care Medicine, University Hospital Bonn, Sigmund-Freud-Straße 25, 53127, Bonn, Germany.
P
P
Markowski
O
O
Boehm
L
L
Goelz
A L
AL
Haesner
H
H
Ehrentraut
K
K
Bauerfeld
N
N
Tran
K
K
Zacharowski
C
C
Weisheit
P
P
Langhoff
M
M
Schwederski
T
T
Hilbert
S
S
Klaschik
A
A
Hoeft
G
G
Baumgarten
R
R
Meyer
P
P
Knuefermann
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D005434:Flow Cytometry; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D016753:Interleukin-10 / Q000096:biosynthesis*; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; C556062:IL10 protein, mouse; D009838:Oligodeoxyribonucleotides; D016753:Interleukin-10