Enhanced tumor necrosis factor--specific and decreased interleukin-10-specific immune responses to LPS during the third trimester of pregnancy in mice E S Vizi 1 , J Szelényi 1 , Zs Selmeczy 1 , Z Papp 2 , Z H Németh 1,3 and G Haskó 1,3 1 Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1450 Budapest, POB 67, Hungary 2 First Department of Obstetrics and Gynecology, Semmelweis University, Faculty of Medicine, Budapest, H-1088 Budapest, Baross u. 27, Hungary 3 Department of Surgery, UMD-New Jersey Medical School, Newark, New Jersey 07103, USA (Requests for offprints should be addressed to E S Vizi, Institute of Experimental Medicine, Hungarian Academy of Sciences, PO Box 67, H-1450 Budapest, Hungary; Email: esvizi@koki.hu) Abstract It is increasingly apparent that there is a bidirectional interaction between the maternal immune system and the reproductive system during pregnancy. Pregnancy is associated with a suppression of maternal specific immune responses, which process underlies the protection of fetal tissues expressing paternally inherited alloantigens. How- ever, recent evidence indicates that the suppression of specific, lymphocyte-mediated immune responses during pregnancy is accompanied by activation of the non- specific arm of the maternal immune response. In the present study, we have investigated the effect of pregnancy on the non-specific immune response induced by bacterial lipopolysaccharide (LPS, endotoxin) in mice. Pregnancy enhanced the LPS-induced production of proinflamma- tory cytokines, including tumor necrosis factor-, inter- leukin (IL)-6, and interferon-. On the other hand, LPS-induced levels of the anti-inflammatory cytokine IL-10 were suppressed in pregnant mice. These alterations in cytokine production correlated with an increased sus- ceptibility for endotoxemic mortality in the pregnant mice. Although adrenergic receptors are important regu- lators of cytokine production in non-pregnant mice, the  2 - and the -adrenoceptor-mediated modulation of cytokine production ceases to operate during pregnancy associated with severe endotoxemia. These data may explain how excessive activation of the non-specific immune responses during pregnancy can contribute to the increased severity of some maternal diseases, including septic shock, and can be an important pathophysio- logical factor in disseminated intravascular coagulation or preeclampsia. Journal of Endocrinology (2001) 171, 355–361 Introduction In his classic 1953 paper, Medawar proposed the concept of the ‘fetal allograft’ to explain the immune relationship between mother and fetus. In this model, immunological interaction between mother and fetus is suppressed, through either lack of fetal-antigen presentation to maternal lymphocytes or maternal lymphocyte suppression. Subsequently, this view of a generalized lymphocyte anergy during pregnancy became more refined, as it was suggested that maternal immune responses would be biased from a T helper (Th)1-type cellular response to a Th2-type, less damaging humoral response (Wegmann et al. 1993). These observations are consistent with clinical evidence that pregnant women with rheumatoid arthritis (a Th1-type autoimmune disease) experience a temporary remission of their symptoms, whereas the severity of systemic lupus erythematosus (a mainly Th2-driven disease) tends to be exacerbated during pregnancy (Ostensen 1999). Although such a decrease in lymphocyte responsiveness explains some of the clinical findings observed in preg- nancy, there are a number of observations suggesting that the model of a shifted Th1/Th2 response does not fully explain the substantial changes in maternal immune sys- tem function. For example, if a decrease in Th1-type immune responses is the dominant feature of the pregnant immune system, then it would be expected that pregnant women would be more susceptible to infection with a variety of intra- and extracellular pathogens. However, this is not the case, because despite the decreased produc- tion of Th1 cytokines, pregnant women are relatively resistant to overwhelming infection (Sacks et al. 1999). Furthermore, in the experimental Shwartzmann reaction, pregnant animals, far from being immunosuppressed, are 355 Journal of Endocrinology (2001) 171, 355–361 0022–0795/01/0171–355  2001 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology.org Downloaded from Bioscientifica.com at 02/04/2019 10:56:44PM via free access