Interleukin-10 gene down-expression in circulating mononuclear cells during infusion of drotrecogin-α activated: a pilot study.
BACKGROUND
The purpose of this study was to investigate the gene expression of interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α) and interleukin-10 (IL-10) in circulating mononuclear cells harvested from septic shock patients on drotrecogin-α activated (DAA) in order to determine whether this treatment has any effect on the inflammation phase.


METHODS
We conducted a prospective cohort study in two intensive care departments. Blood samples were collected at inclusion (T1) and 36 hours later (T2) to measure plasma cytokines and the changes in intracellular TNF-α, IL-10 and IFN-γ mRNA expressions using the real-time quantitative polymerase chain reaction (RT-qPCR). Thirty-two septic shock patients were included: 16 with DAA at 24 μg/kg/h for 96 hours (DAA+) and 16 control (DAA-) eligible but contraindicated for DAA because of low platelet count.


RESULTS
The basal characteristics were similar in both groups: mortality (50%), plasma cytokine concentrations, and baseline IFN-γ, TNF-α and IL-10 mRNA expressions (DAA+ vs. DAA-). At T2, there was a significant IFN-γ gene down-regulation in DAA+ but not in DAA- patients (-0.34 (-0.62; +1.54) vs. +1.41 (+0.35; +5.87), P = 0.008). In survivors, DAA administration was associated with a down-expression of both IFN-γ (-0.65 (-0.93; 0.48) vs. +0.7 (-0.04; +1.26), P = 0.01) and IL-10 (-0.78 (-0.92; -0.6) vs. -0.18 (-0.68; +0.46), P = 0.038). In the non-survivors, DAA infusion was associated with IL-10 over-expression when compared with survivors (+0.54 (-0.35; +11.52) vs. -0.78 (-0.92; -0.6), P < 0.001).


CONCLUSIONS
In this study, lack of IL-10 gene down-expression despite a 36-hour infusion of DAA is an ominous sign in septic shock patients suggesting that DAA is not able to reverse the outcome. Our results suggest that DAA can decrease the expression of anti-inflammatory cytokines in septic shock patients. IL-10 or IFN-γ gene down-expression could represent markers of DAA response.
Lavaux
Thomas
T
Department of Biochemistry and Molecular Biology, Hôpital de Hautepierre et Université de Strasbourg, Avenue Molière, 67098 Strasbourg, France. thomas.lavaux@chru-strasbourg.fr
Bilbault
Pascal
P
Launoy
Anne
A
Gaub
Marie-Pierre
MP
Oudet
Pierre
P
Schneider
Francis
F
D000368:Aged; D015331:Cohort Studies; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D016753:Interleukin-10 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D010865:Pilot Projects; D011446:Prospective Studies; D011486:Protein C / Q000008:administration & dosage*; D011994:Recombinant Proteins / Q000008:administration & dosage; D012772:Shock, Septic / Q000097:blood* / Q000188:drug therapy / Q000473:pathology
D011486:Protein C; D011994:Recombinant Proteins; D016753:Interleukin-10; C421124:drotrecogin alfa activated
Crit Care Med. 2007 Jan;35(1):69-75
17133181
Crit Care. 2010;14(1):R15
20144219
Crit Care. 2005;9 Suppl 4:S38-45
16168074
J Immunol. 2008 Aug 1;181(3):2165-73
18641355
Crit Care Med. 2005 Dec;33(12 Suppl):S468-71
16340424
Lancet. 2005 Jan 1-7;365(9453):63-78
15639681
JAMA. 1993 Dec 22-29;270(24):2957-63
8254858
JAMA. 1996 Sep 11;276(10):802-10
8769590
N Engl J Med. 2001 Mar 8;344(10):699-709
11236773
Crit Care Med. 2003 Apr;31(4):1250-6
12682500
Arch Intern Med. 2002 May 13;162(9):1028-32
11996613
Methods. 2001 Dec;25(4):402-8
11846609
Intensive Care Med. 2000;26 Suppl 1:S124-8
10786969
Ann Pharmacother. 2005 Feb;39(2):262-7
15632220
Shock. 2008 Oct;30 Suppl 1:73-7
18704004
Crit Care Med. 2002 May;30(5 Suppl):S288-93
12004250