Inhibition of Dipeptidyl Peptidase IV (DP IV, CD26) Activity Abrogates Stress‐Induced, Cytokine‐Mediated Murine Abortions

Abstract

In the CBA × DBA/2 mouse model, stress‐triggered abortions are mediated by a Th1‐like cytokine response of decidual lymphocytes. The factors that determine the cytokine pattern leading to abortion are currently unknown. Dipeptidyl Peptidase IV (DP IV) enhances Th1‐cytokine responses and impairs the evolvement of a Th2 cytokine profile. The T‐cell‐activation antigen, CD26, possesses DP IV activity. The aim of the present study was to investigate the role of DP IV activity and CD26‐positive decidual lymphocytes in murine stress‐triggered abortions by inhibition of DP IV activity. DBA/2‐mated CBA mice were stressed on day 5.5 of pregnancy and received daily injections of an inhibitor of DP IV activity, Ile‐thiazolidide (20 µmol/kg). On day 13 of gestation, the animals were sacrificed and the percentage of implants and abortions documented. CD26‐positive lymphocytes in spleen and uterine decidua and the intracellular cytokines interferon (IFN)‐γ and interleukin (IL)‐10 were determined by flow cytometry. Stressed and nonstressed animals receiving an inactive stereoisomeric form were used as controls. In mice receiving the DP IV inhibitor, stress failed to boost the abortion rate (37.2% versus 13.6%, P < 0.01). IFN‐γ producing cells were increased in stressed animals, but returned to the baseline upon the inhibition of DP IV. The number of IL‐10 producing cells was reduced in stressed animals, independent from DP IV inhibition.

Depletion of CD8+ Cells Abolishes the Pregnancy Protective Effect of Progesterone Substitution with Dydrogesterone in Mice by Altering the Th1/Th2 Cytokine Profile

“…This result confirms the notion of Th1 cytokines deleterious for pregnancy maintenance (21). Indeed, other Th1 cytokines, e.g., IFN-␥, increased after stress exposure in murine matings (23,50). Interestingly, Tangri and Raghupathy (51) demonstrated that the placenta of an abortionprone mating such as CBA/J ϫ DBA/2J produced high levels of TNF-␣ and IFN-␥, whereas in low abortion mating, e.g., CBA/J ϫ BALB/c, IL-10 is dominant.…”

The Therapeutic Potential of Inhibitors of Dipeptidyl Peptidase IV (DPP IV) and Related Proline-Specific Dipeptidyl Aminopeptidases

“…The DPP IV inhibitors Ile-thiazolidide (2) and Ilepyrrolidine-2-nitrile abrogate stress-induced abortions and an enhanced production of interferon-γ in mice [273,274].…”

Activation Antigens during the Proliferative and Secretory Phases of Endometrium and Early-Pregnancy Decidua

“…As most of the lymphocytes in endometrium and decidua are large granular lymphocytes, the absence of CD26 can be expected. Stress-triggered abortions are reported to be mediated by a Th1-like cytokine response of decidual lymphocytes, and CD26 is believed to enhance Th1 cytokine responses [37,38] . The presence of decidual CD26+ lymphocytes is reported in spontaneous abortions and, confusingly, also in normal pregnancy samples (but more prevalent in abortions), indicating a critical role for CD26 in pregnancy failure by inducing a Th1 local response [39,40] .…”