Heparin inhibits interferon-γ signaling in human endometrial stromal cells by interference with the cellular binding of interferon-γ.
OBJECTIVE
To examine the impact of heparins on interferon-γ (IFN-γ) signaling in human endometrial stromal cells (ESCs) in vitro.


METHODS
In vitro experiment.


METHODS
Research laboratory at a medical university center.


METHODS
Premenopausal women undergoing hysterectomy for benign reasons.


METHODS
The ESCs were isolated from hysterectomy specimens, decidualized in vitro using P and 17β-E(2), and incubated with recombinant IFN-γ, unfractionated heparin, and low molecular weight heparins (LMWHs).


METHODS
Interferon response factor 1 (IRF-1) and N-myc interactor (Nmi) messenger RNA (mRNA) were measured using real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Phosphorylation of signal transducer and activator of transcription 1 (STAT-1) was detected by an in-cell Western assay, expression of the IFN-γ receptor by flow cytometry. Cell-bound IFN-γ was determined in lysates by an ELISA.


RESULTS
Heparin and LMWHs inhibit the IFN-γ-mediated induction of IRF-1, but not Nmi in undifferentiated and decidualized ESCs. The phosphorylation of signal transducer and activator of transcription 1 STAT-1 upon IFN-γ stimulation is inhibited as well. Heparin has no effect on the IFN-γ receptor in ESCs, but inhibits the binding of IFN-γ to the cells.


CONCLUSIONS
Unfractionated heparin, as well as LMWHs, are able to inhibit IFN-γ signaling in human ESCs and therefore might be clinically interesting agents to modulate the actions of this proinflammatory cytokine at the implantation site.
Fluhr
Herbert
H
Department of Obstetrics and Gynecology, University of Greifswald, Greifswald, Germany.
Spratte
Julia
J
Heidrich
Stephanie
S
Ehrhardt
Jens
J
Steinmüller
Frauke
F
Zygmunt
Marek
M
D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004717:Endometrium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000502:physiology*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D007371:Interferon-gamma; D006493:Heparin