ABSTRACT
It has been proposed that progesterone (P4) induces the suppression of immune responses, particularly during pregnancy. However, knowledge about the mechanisms involved has remained largely elusive. We demonstrate herein that peripheral blood NK (PBNK) cells express both classical progesterone receptor (PR) isoforms and are specifically affected by the actions of P4 through two apparently independent mechanisms. Progesterone induces caspase-dependent PBNK cell death, which is reversed by two different anti-progestins, ZK 98.299 and RU 486, supporting the involvement of classical PR isoforms. It was suggested that CD56(bright)CD16(-) killer Ig-like receptor (KIR)(-) NK cells might represent precursor cells, which, upon activation, acquire the features of a more mature NK subset expressing KIR receptors. The present study demonstrates that PR expression seems to be restricted to more mature KIR(+) PBNK cells. The expression of PR had a functional counterpart in the suppressive effect of P4 on IL-12-induced IFN-gamma secretion. This cytokine suppression was mainly observed in KIR(+) PBNK cells, without affecting the high secretion of IFN-gamma by CD56(bright) PBNK cells. The lack of PR expression on CD56(bright)KIR(-) PBNK cells provides an additional phenotypic marker to test the idea that they might represent the PBNK precursors selectively recruited into the endometrium where they differentiate to become the uterine NK cells. Additionally, these findings may be relevant to NK cell function in viral immunity, human reproduction, and tumor immunity.
Subject(s)
Apoptosis , Killer Cells, Natural/metabolism , Lymphocyte Subsets/metabolism , Progesterone/metabolism , Receptors, Progesterone/metabolism , Adult , Female , Humans , Interferon-gamma/immunology , Interferon-gamma/metabolism , Interleukin-12/immunology , Interleukin-12/metabolism , Killer Cells, Natural/drug effects , Killer Cells, Natural/immunology , Lymphocyte Subsets/drug effects , Lymphocyte Subsets/immunology , Male , Mifepristone/pharmacology , Signal TransductionABSTRACT
From an immunological point of view, the healthy liver has been usually associated with the phenomenon of tolerance. A microenvironment of regulatory cytokines produced by liver Kuppfer cells and liver sinusoidal endothelial cells has contributed, together with resident dendritic cells, to generate a tolerogenic environment in this tissue. In this review we discussed the intrahepatic responses to different sorts of liver injury, such as hepatotrophic viruses, alcohol or putative self-antigens. In each case we analyzed the impact of different cytokines in the clinical outcome of the different pathological situations.
