Cemil AKGÜL, Pervin VURAL, Yıldırım Neslihan SARAL

Plasma pro-inflammatoryand anti-inflammatory cytokıne levels in preeclampsia

Amaç: Sitokinler normal gebeliğin sürdürülmesi ve patolojik durumların ortaya çıkmasında önemli rol oynar. Bu çalışmada preeklampside plazma sitokin paternini incelemek ve hastalığın seyri ile bir ilişkisi olup olmadığını değerlendirmek hedeflenmiştir. Gereç ve yöntem: 25’i sağlıklı ve gebe olmayan (NP), 20’si normotensif gebe (NTP), ve 20’si preeklamptik gebe (PEP) olmak üzere toplam 65 kadının plazma örneklerinde TNFα, IL-1β, IL-12, IL-4 ve IL-10 konsantrasyonları tayin edildi. İstatistiksel değerlendirme Student’s t-, Kruskal-Wallis, Mann-Whitney U- ve Spearman korelasyon testleri ile gerçekleştirildi.Bulgular: NP kadınlara kıyasla, PEP’de pro-inflamatuar ve Th1 sitokinleri olan TNFα, IL-1β, IL-12 artışı ile birlikte anti-inflamatuar ve Th2 sitokinleri olan IL-4 ve IL-10 de artmaktadır. Bununla birlikte, NTP’ye kıyasla PEP’de anti-inflamatuar IL-4 ve IL-10 düzeyleri artmaktadır. Preeklampsi grubunda IL-1β/ IL-10; TNFα/IL-12 arasında pozitif; IL-4/sistolik kan basıncı ve IL-4/LDH arasında ise negatif korelasyon bulundu.Sonuçlar: Anti-inflamatuar sitokin artışı pro-inflamatuar sitokinlerin neden olduğu endotel disfonksiyonuna karşı koyan bir kompensatuar mekanizma olabilir. Anti-inflamatuar sitokinler ile kan basıncı veya bazı karaciğer enzimleri arasında bulunan negatif korelasyon, plazma sitokin düzeyleri ve hastalığın seyri arasında bir ilişki olabileceğini ortaya koymaktadır. Bununla birlikte, preeklampside anne plazmasında IL-4 ve IL-10 konsantrasyonlarının artışının, Th1/Th2 sitokin dengesini etkileyerek, maternal imünorejeksiyondan korumaya çalışan bir cevap olduğunu söyleyebiliriz.

Preeklampside plazma pro-inflamatuar ve anti-inflamatuar sitokin düzeyleri

Objective: Cytokines appear to contribute to the maintenance of normal pregnancy and development of pathological conditions. The aim of this study was to evaluate plasma cytokine pattern in preeclampsia and whether there is any relationship with disease severity or not. Materials and methods: Plasma samples of 65 women (25 healthy nonpregnant (NP), 20 normotensive pregnant (NTP) and 20 preeclamptic pregnant (PEP) women) were investigated by means of TNFα, IL-1β, IL-12, IL-4 and IL-10 concentrations. Statistical significance was analysed by Student’s t-, Kruskal- Wallis, Mann-Whitney U- and Spearman correlation tests.Results: In PEP in comparison with NP women, together with elevation of pro-inflammatory TNFα, IL-1β and IL-12 (Th1 cytokines), there is an increase of anti-inflammatory IL-4 and IL-10 (Th2 cytokines). In addition, there is an increase of anti-inflammatory IL-4 and IL-10 levels in PEP in comparison with NTP. Among the preeclamptic group there is a significant positive correlation between IL-1β/IL-10 and TNFα/IL-12; also, a significant negative correlation between IL-4/systolic blood pressure, IL-4/LDH.Conclusions: The rise of anti-inflammatory cytokines probably is a compensatory mechanism by which IL-4 and IL-10 counteract to pro-inflammatory cytokines, and thus balance their endothelium destroying effects. The presence of negative correlation between anti-inflammatory cytokines and blood pressure or some liver enzymes suggests that there is probably a relationship between plasma cytokines and disease severity. On the other hand, elevated maternal plasma IL-4 and IL-10 concentrations in preeclampsia may be a response to improve altered Th1/Th2 balance and to protect from maternal immunorejection.

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1) Abbas AK, Lichtman AH, Pober JS: Cellular and Molecular Immunology. 2nd e. Philadelphia, WB Saunders, 1994.
2) Bozychowski AM, Croy BA, Chan WL, Redman CW, Sargent IL. Changes in systemic type 1 and 2 immunity in normal pregnancy and pree-clampsia may be mediated by natural killer cells. Eur j Immunol 2005; 35: 3054-3063.
3) Chaouat G, Menu E, Clark DA, Dy M, Minkowski M, Wegmann TG. Control of fetal survival in CBAxDBA/2 mice by lymphokine therapy. J Reprod Fertil 1990; 89: 447-458.
4) Chen G, Wilson R, McKillop JH, Walker JJ. The role of cytokines in the production of prostacyclin and thromboxane in human mononuclear cells. Immunol Invest 1994; 23: 269-279.
5) Chen G, Wilson R, Wang SH, Zheng HZ, Walker JJ, McKillop JH. Tumor necrosis factor-alpha (TNFα) gene polymorphism and expression in pre-eclampsia. Clin Exp Immunol 1996; 104: 154-159.
6) Conrad KP, Miles TM, Benyo DF. Circulating levels of immunoreactive cytokines in women with preeclampsia. Am J Reprod Immunol 1998; 40: 102-111.
7) Dinarello CA. Interleukin-1, interleukin-1 receptors and interleukin-1 receptor antagonist. Int Rev Immunol 1998; 16: 457-499.
8) Dong MY, Shi XL, He J, Wang ZP, Xie X, Wang HZ. Imbalance of serum T helper1- and 2-type cytokines in preeclampsia and gestational hypertension. Zhejiang Da Xue Xue Bao Yi Xue Ban 2005; 34: 488-491.
9) Ellis J, Wennerholm MB, Bengtsson A, Lilja H, Pettersson A, Sultan B, Wennerger M,Hagber H. Levels of dimethylarginines and cytokines in mild and severe preeclampsia. Acta Obstet Gynecol Scand 2001; 80: 602-608.
10) Freeman DJ, McManus F, Brown EA, t al. Short- and long-term changes in plasma inflammatory markers associated with preeclampsia. Hypertension 2004; 43: 708-714.
11) Greig PC, Herbert WNP, Robinette BL, Teot LA. Amniotic fluid interleukin-10 concentrations increase though pregnancy and are elevated in patients with preterm labor associated with intrauterine infection. Am J Obstet Gynecol 1995; 173: 1223-1227.
12) Haimovici F, Hill JA, Anderson DJ. The effects of soluble products of activated lymphocytes and macrophages on blastocyst implantation events in vitro. Biol Reprod 1991; 4: 69-75.
13) Hefler L, Temper CB, Gregg AR. Polymorphisms within the interleukin-1β gene cluster and preeclampsia. Obstet Gynecol 2001; 97: 664-668.
14) Hennessay A, Pulmore HL, Simmons LA, Painter DM. Adeficiency of plasental IL-10 in preeclampsia. J Immunol 1999; 163: 3491-3495.
15) Heyl W, Handt S, Reister F, Gehlen J, Schröder W, Mittermayer C, Rath Wet al. Elevated soluble adhesion molecules in women with preeclampsia. Do cytokines like tumor necrosis factor-α and interleukin -1β cause endothelial activation? Eur J Obstet Gynecol 1999; 86: 35-41.
16) Huang SJ, Schatz F, Masch R, Rahman M, Buchwalder L, Niven-Fairchild T, Tang C, Abrahams WM, Krikun G, Lockwood CJ. Regulation of chemokine production in response to pro-inflammatory cytokines in first trimester decidual cells. J Reprod Immunol 2006; 72: 60-73.
17) Jonsson Y, Ruber M, Matthiesen L, Berg G, Nieminen K, Sharma S, Ernerudh J, Ekerfelt C. Cytokine mapping of sera from women with preeclampsia and normal pregnancies. J Reprod Immunol 2006; 70: 83-91.
18) Kilpatrick DC. HLA-dependent TNF secretory response may provide an immunogenetic link between preeclampsia and type 1 diabetes mellitus. Dis Markers 1996; 13: 43-47.
19) Mosmann TR. Interleukin-10. In: Thomson AW, editor. The cytokine handbook. California: Academic Press 1994; 223-237.
20) Opsjon SL, Austgulen R, Waage A. Interleukin-1, interlukin-6 and tumor necrosis factor at deliery in preeclamptic disorders. Acta Obstet Scand 1995; 74: 19-26.
21) Raghupathy R, Makhseed M, Azizieh F, Hassan N, Al-Azemi M, Al-Shamali E. Maternal Th1- and Th2- type reactivity to placental antigens in normal human pregnancy and unexplained recurrent spontaneous abortions. Cell Immunol 1999; 196: 122-130.
22) Reinehart BK, Terrone DA, Lagoo-Deenadaylan S, Barber WH, Hale EA, Martin JN, Bennet WA. Expression of placental cytokines tumor necrosis factor alfa, interleukin 1 beta, and interleukin 10 is increased in preeclampsia. Am J Obstet Gynecol 1999; 181: 915-20.
23) Roberts JM, Redman CWG. Preeclampsia: more than pregnancy-induced hypertension. Lancet 1993; 341: 1447-1454.
24) Sad S, Mosmann TR. Interleukin (IL) 4, in the absence of antigen stimulation, induces an anergy-like state in differentiated CD8+ TC1 cells: loss of IL-2 synthesis and autonomous proliferation but but retention of cytotoxicity and synthesisi of other cytokines. J Exper Med 1995; 182: 1505-1515.
25) Seki H, Matuoka K, Inooku H, Takeda S. TNF-alpha from monocyte of patients with pre-eclampsia-induced apoptosis in human trophoblast cell line. J Obstet Gynaecol Res 2007; 33: 408-416.
26) Vane JR, Anggard EE, Botting RM. Regulatory functions of the vascular endothelium. N Engl J Med 1990; 323: 27-36.
27) Vural P, Akgul C, Canbaz M. Urinary PGE2 and PGF2α levels and renal functions in preeclampsia. Gynecol Obstet Invest 1998; 45: 237-241.
28) Vural P. Nitric oxide/endothelin-1 in preeclampsia. Clinica Chimica Acta 2002; 317: 65-70.
29) Wang Y, Walsh SW, Kay HH. Placental lipid peroxides and thromboxane are increased and prostacyclin is decreased in women with preeclampsia. Am J Obstet Gynecol 1992; 167: 946-949.
30) Yelevarthi KK, Chen G, Yang Y, Cowlet BD, Fiscback JL, Hunt JS. Tumor necrosis factor-αmRNAand protein in rat uterine and placental cells. J Immunol 1991; 146: 3840-3848.
31) Yui J, Garcia- Lloret M, Wegmann TG, Guilbert LJ. Cytotoxicity of tumor necrosis factor-alpha and gamma-interferon against primary human placental trophoblasts. Placenta 1994, 15: 819-835.