Regulatory effects of estriol on T cell migration and cytokine profile: inhibition of transcription factor NF-κB
Introduction
There is well-established clinical evidence indicating that pregnancy has a protective effect on the disease activity of MS Abramsky, 1994, Confavreux et al., 1998. In particular, patients with relapsing-remitting MS tend to have less frequent exacerbation during gestation and especially during the third trimesters. However, the frequency of relapse increases in the postpartum period, especially in the first 3 months before it returned to pre-pregnancy rate at about 10 months after delivery (Confavreux et al., 1998). The protective effect of pregnancy is also found in other autoimmune conditions. For example, a tendency for gestational remission and for postpartum exacerbation was also described in rheumatoid arthritis, myasthenia gravis and autoimmune thyroditis. The same beneficial association of pregnancy and autoimmunity is also seen in autoimmune animal models. This is indicated by the resistance of pregnant animals to the induction of experimental autoimmune encephalomyelitis (EAE) while the same animals are susceptible to EAE during postpartum period (Abramsky, 1994).
It has long been speculated that the favorable effect of pregnancy on the clinical activity of MS is at least partially attributable to sex hormones produced at pregnant state. One of the important hormones that are produced at large quantities during pregnancy is estriol. It is produced by feto-placental unit and accounts for 90% of all estrogens produced during pregnancy. The production of estriol in pregnancy is 1000 times more than that in the nonpregnant state. It has been demonstrated that there is an increased production of Th2 cytokines, such as IL-4 and IL-10 during pregnancy in both humans and laboratory animals, which is consistent with reduced cellular immunity and inflammatory responses during pregnancy (Wegmann et al., 1993). There is preliminary evidence that estriol has a modulatory effect on the cytokine profile of T cells recognizing myelin antigens Gilmore et al., 1997, Correale et al., 1998. Kim et al. (1999) reported recently that administration with estriol in rodents resulted in resistance to the induction of EAE, which correlated with an increased in vivo production of IL-10. Similar in vivo effect of estriol was also reported by Bebo et al. (2000). Thus, the preliminary results accumulated so far suggest that estriol may play an important role in the functional alteration of the immune system during pregnancy. Another phenomenon associated with normal pregnancy is the decreased trafficking of immune cells. It has been noted for years that trafficking of immune cells is reduced/restricted during pregnancy. However, the cellular and molecular mechanism underlying the association of the decreased migration of immune cells and pregnancy is not understood. It is conceivable that regulatory mechanism by which the immune system is modulated by sex hormones, such as estriol, to avoid/reduce reactions to fetal alloantigens encoded by genes inherited from the father, may provide an important lesson in our attempts to explore the role of pregnancy-related hormones in the treatment for MS and other autoimmune conditions.
This study was undertaken to evaluate potential regulatory effects of estriol on the transmigratory behavior and cytokine profile of autoreactive T cells as these functional properties are directly associated with the inflammatory nature of the T cells. We examined transmigration and the cytokine profile of unprimed T cells and myelin basic protein (MBP)-reactive T cells obtained from MS patients in the presence of estriol used at a concentration range typical of pregnancy. The action of estriol on MMP-9 and the various cytokines prompted us to further investigate whether it could regulate nuclear transcription factor κB (NF-κB), which is known to control the expression of multiple immune-related genes, including cytokines and matrix metalloproteinase (MMP) (McKay and Cidlowski, 1999). NF-κB is composed of at least five protein subunits, p50, p52, RelA (p65), c-Rel and RelB, which all share a Rel homology domain that is responsible for hetero- or homodimerization, DNA binding and nuclear translocation (Baeuerle and Henkel, 1994). In most cells, NF-κB exists in an inducible form in the cytoplasm complex coupled to its inhibitor, IκB kinase, that masks the nuclear location signal necessary for nuclear translocation of NF-κB (Beg et al., 1992). Activation of NF-κB is a rapid process involving proteolytic degradation of IκBs and translocation of NF-κB in the nucleus, where it binds to κB motifs to up-regulate the expression of target genes (Beg et al., 1993). The κBα gene contains several κB sites in the promoter and its expression is increased following NF-κB activation (Le bail et al., 1993), thus closing the autoregulatory loop. In this study, further characterization confirmed that estriol inhibited NF-κB activity, which correlated with decreased IκB degradation. The findings reported here provide important indications that estriol is a potent T cell regulator, which may interact with signaling molecules in the NF-κB pathway to regulate trafficking and cytokine profile of inflammatory/autoreactive T cells.
Section snippets
Reagents
Estriol and 17α-estradiol were obtained in purified form from Sigma (St. Louis, MO). Tamoxifen, a specific estrogen receptor antagonist, was purchased from Barr Laboratories (Pomona, NY). AIM-V serum-free medium was from Life Technologies (Grand Island, NY). Recombinant human TNFα was obtained from PharMingen (San Diego, CA). Antibodies to NF-κB p65 and p50 were obtained from Santa Cruz Biotechnology (Santa Cruz, CA). Cytokine ELISA kits were purchased from PharMingen.
Patients and control subjects
Blood specimens were
Regulatory effect of estriol on T cell migration and the expression of MMP-9
We first examined whether estriol would affect T cell transmigration of a cloned MBP-reactive T cell line (2E3) derived from an MS patient, and unprimed T cell preparations purified from three relapsing-remitting MS patients pre-selected for high spontaneous T cell transmigration (Zang et al., 2000). T cells were pretreated with estriol and 17α-estradiol, an inactive form of estrogen as a control, for 16 h and examined for transmigration using the Boyden chamber system (Materials and methods).
Discussion
The findings described in this study provide important insights in our understanding of the role of estriol in regulation of the immune system, which may have implications in the development of new treatment modelity for MS. That is, the immune system encounters a unique situation in pregnant state where it must adapt through the sex hormones or other regulators of the immune system to avoid reactions to fetal alloantigen encoded by genes inherited from the father. The key processes include Th2
Acknowledgements
The work was supported in part by the Richardson Foundation. We thank Ms. R. Robinson and Ms. S. Li for technical assistance.
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