![]() ![]() Progesterone has been shown to upregulate the differentiation of DCs as measured by increased endocytic activity from bone marrow precursors, although following LPS stimulation, an immature phenotype was maintained under the influence of progesterone as demonstrated by decreased MHC class II, CD40, CD54, and CD80 expression ( 23, 24). Given the paramount importance of DCs in linking, as well as driving, the innate and adaptive immune response and the well-documented ability of progesterone to modulate immune activity, there have been surprisingly few studies investigating how progesterone specifically modulates DC maturation and function. This change in the hormonal milieu is thought to play a major role in skewing the maternal immune response to a Th2 and T regulatory phenotype ( 12, 13), influenced in part by actions of hormones on a number of hematopoietic cells including DCs ( 14, 15). The microenvironment created during pregnancy differs from the normal physiological situation, particularly with regard to circulating hormones, and levels of glucocorticoids, estrogen, and progesterone are all increased. ![]() DCs have been demonstrated around the fetomaternal interface, and studies have shown that in this situation, their function is altered to favor production of regulatory cytokines, such as IL-10, and reduce secretion of inflammatory cytokines, such as IL-12 ( 10, 11). In addition, during pregnancy, T regulatory cells specific for fetal allograft Ags are involved in expression of tolerance to the fetus ( 8, 9). The induction of a Th2 response has been demonstrated to occur in the vicinity of the placenta during mammalian pregnancy, and disruption of this has been associated with abortion ( 6, 7). Overall, these studies demonstrate that progesterone can differentially regulate the signaling pathways employed by TLR3 and TLR4 agonists to affect costimulatory molecule expression and cytokine production. Stimulation of the PR (with progesterone and norgestrel) by pretreatment of DCs was found to sustain IFN regulatory factor-3 phosphorylation following TLR3 ligation, but not TLR4 ligation. Of particular significance was that progesterone was able to significantly inhibit TLR3- but not TLR4-induced CD40 expression in bone marrow-derived DCs. Progesterone was found to downregulate, albeit with different sensitivities, both TLR3- and TLR4-induced IL-6 production entirely via the GR, but IL-12p40 production via either the GR or PR. We compared the ability of progesterone to modulate murine bone marrow-derived DC cytokine production (IL-6 and IL-12) and costimulatory molecule expression (CD40, CD80, and CD86) induced by either TLR3 or TLR4 ligation and determined whether activity was via the progesterone receptor (PR) or glucocorticoid receptor (GR) by comparative studies with the PR-specific agonist norgestrel and the GR agonist dexamethasone. ![]() The role of progesterone in modulating dendritic cell (DC) function following stimulation of different TLRs is relatively unknown. ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |