TWEAK appears as a modulator of endometrial IL-18 related cytotoxic activity of uterine natural killers.
BACKGROUND
TWEAK (Tumor necrosis factor like WEAK inducer of apoptosis) is highly expressed by different immune cells and triggers multiple cellular responses, including control of angiogenesis. Our objective was to investigate its role in the human endometrium during the implantation window, using an ex-vivo endometrial microhistoculture model. Indeed, previous results suggested that basic TWEAK expression influences the IL-18 related uNK recruitment and local cytotoxicity.


RESULTS
Endometrial biopsies were performed 7 to 9 days after the ovulation surge of women in monitored natural cycles. Biopsies were cut in micro-pieces and cultured on collagen sponge with appropriate medium. Morphology, functionality and cell death were analysed at different time of the culture. We used this ex vivo model to study mRNA expressions of NKp46 (a uNK cytotoxic receptor) and TGF-beta1 (protein which regulates uNK cytokine production) after adjunction of excess of recombinant IL-18 and either recombinant TWEAK or its antibody. NKp46 protein expression was also detailed by immunohistochemistry in selected patients with high basic mRNA level of IL-18 and either low or high mRNA level of TWEAK. The NKp46 immunostaining was stronger in patients with an IL-18 over-expression and a low TWEAK expression, when compared with patients with both IL-18 and TWEAK high expressions. We did not observe any difference for TWEAK expression when recombinant protein IL-18 or its antibody was added, or conversely, for IL-18 expression when TWEAK or its antibody was added in the culture medium. In a pro-inflammatory environment (obtained by an excess of IL-18), inhibition of TWEAK was able to increase significantly NKp46 and TGF-beta1 mRNA expressions.


CONCLUSIONS
TWEAK doesn't act on IL-18 expression but seems to control IL-18 related cytotoxicity on uNK cells when IL-18 is over-expressed. Thus, TWEAK appears as a crucial physiological modulator to prevent endometrial uNK cytotoxicity in human.
INSERM, U782, Implantation et Dialogue Materno-Fœtal, University Paris-Sud, UMR-S0782, Hôpital Antoine Béclère, Clamart, France.
Marie
M
Petitbarat
Mona
M
Rahmati
Valérie
V
Sérazin
Sylvie
S
Dubanchet
Corinne
C
Morvan
Robert
R
Wainer
Philippe
P
de Mazancourt
Gérard
G
Chaouat
Jean-Michel
JM
Foidart
Carine
C
Munaut
Nathalie
N
Lédée
D002478:Cells, Cultured; D000074049:Cytokine TWEAK; D003602:Cytotoxicity, Immunologic; D004717:Endometrium / Q000166:cytology* / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D020382:Interleukin-18 / Q000032:analysis / Q000235:genetics*; D055627:Natural Cytotoxicity Triggering Receptor 1; D055611:Natural Killer T-Cells / Q000276:immunology*; D012333:RNA, Messenger / Q000032:analysis; D053773:Transforming Growth Factor beta1; D048069:Tumor Necrosis Factors / Q000502:physiology*; D014599:Uterus / Q000166:cytology* / Q000276:immunology
D000074049:Cytokine TWEAK; D020382:Interleukin-18; C112260:NCR1 protein, human; D055627:Natural Cytotoxicity Triggering Receptor 1; D012333:RNA, Messenger; C109743:TNFSF12 protein, human; D053773:Transforming Growth Factor beta1; D048069:Tumor Necrosis Factors
Genome Biol. 2002 Jun 18;3(7):RESEARCH0034
12184808
Hum Reprod. 2004 Nov;19(11):2605-14
15465835
Mol Hum Reprod. 1999 May;5(5):452-8
10338368
J Biol Chem. 1999 Mar 26;274(13):8455-9
10085077
Nat Rev Drug Discov. 2008 May;7(5):411-25
18404150
J Biol Chem. 1997 Dec 19;272(51):32401-10
9405449
Placenta. 2005 Feb-Mar;26(2-3):262-7
15708128
Hum Reprod. 2004 Feb;19(2):330-8
14747176
Cytokine Growth Factor Rev. 2003 Jun-Aug;14(3-4):241-9
12787562
Hum Reprod. 2001 May;16(5):836-45
11331626
Biol Reprod. 2001 Mar;64(3):831-8
11207198
Am J Reprod Immunol. 1997 Jun;37(6):463-70
9228303
Reproduction. 2003 Aug;126(2):149-60
12887272
Hum Reprod. 2005 Apr;20(4):864-71
15665014
Semin Reprod Med. 2007 Nov;25(6):445-53
17960529
Cytokine. 2007 Oct;40(1):1-16
17981048
Placenta. 2001 Sep-Oct;22(8-9):663-72
11597186
J Leukoc Biol. 2004 Sep;76(3):667-75
15178706
Fertil Steril. 2005 Mar;83(3):598-605
15749487
J Reprod Fertil. 1994 Jul;101(2):327-32
7932366
J Immunol. 2008 Aug 1;181(3):1869-76
18641324
Cell. 2001 Feb 23;104(4):487-501
11239407
Am J Obstet Gynecol. 1992 Dec;167(6):1774-80
1471697
Dev Biol. 2003 Aug 1;260(1):176-90
12885563
J Leukoc Biol. 2006 Sep;80(3):572-80
16816146
Am J Reprod Immunol. 1996 Mar;35(3):256-7
8962656
Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):10129-33
7937850
Fertil Steril. 2010 Aug;94(3):1141-3
20004376
J Reprod Immunol. 2008 Jan;77(1):57-62
17961712
Fertil Steril. 1992 Sep;58(3):537-42
1521649