The influence of prostaglandin E2 on the production of IFN-γ by bovine CD4(+), CD8(+) and WC1(+) T cells.

The aim of these studies was to assess the influence of prostaglandin E2 (PGE2) on the production of interferon-gamma (IFN-γ) by bovine CD4(+), CD8(+), and WC1(+) T cells and furthermore, should this effect exist, to identify the E-prostanoid (EP) receptor subtype(s) responsible for this influence. We here report that exposure of bovine peripheral blood mononuclear cells (PBMCs) to PGE2 significantly and dose-dependently decreased the percentage of IFN-γ-producing CD4(+) and CD8(+) T cells. It was also shown that PGE2 reduced IFN-γ production by WC1(+) T cells, but this effect was not dose dependent. The impairment of IFN-γ production should be recognized as an anti-inflammatory and immunosuppressive action, thus the obtained results confirm the paradoxical status of PGE2 as a proinflammatory factor with immunosuppressive activity. The blockade of EP1, EP2, EP3, and EP4 receptors did not prevent PGE2-induced reduction of IFN-γ production by CD4(+) and CD8(+) T cells, indicating that this effect of PGE2 is not mediated through EP receptors. On the contrary, the blockade of either EP2 or EP4 receptors, but not EP1 or EP3 receptors, prevented the PGE2-induced reduction of percentage of IFN-γ-producing WC1(+) T cells. These findings indicate that the ability of PGE2 to impair IFN-γ production by WC1(+) T cells is mediated via EP2 and EP4 receptors. These results suggest the possibility of pharmacological manipulation of IFN-γ production by WC1(+) T cells via selective antagonists and agonists of EP2 and EP4 receptors.

IκB kinase ß inhibitor, IMD-0354, prevents allergic asthma in a mouse model through inhibition of CD4(+) effector T cell responses in the lung-draining mediastinal lymph nodes.

IκB kinase (IKK) is important for nuclear factor (NF)-κB activation under inflammatory conditions. It has been demonstrated that IMD-0354, i.e. a selective inhibitor of IKKß, inhibited allergic inflammation in a mouse model of ovalbumin (OVA)-induced asthma. The present study attempts to shed light on the involvement of CD4(+) effector (Teff) and regulatory (Treg) T cells in the anti-asthmatic action of IMD-0354. The animals were divided into three groups: vehicle treated, PBS-sensitized/challenged mice (PBS group); vehicle treated, OVA-sensitized/challenged mice (OVA group); and IMD-0354-treated, OVA-sensitized/challenged mice. The analyzed parameters included the absolute counts of Treg cells (Foxp3(+)CD25(+)CD4(+)), activated Teff cells (Foxp3(-)CD25(+)CD4(+)) and resting T cells (CD25(-)CD4(+)) in the mediastinal lymph nodes (MLNs), lungs and peripheral blood. Moreover, lung histopathology was performed to evaluate lung inflammation. It was found that the absolute number of cells in all studied subsets was considerably increased in the MLNs and lungs of mice from OVA group as compared to PBS group. All of these effects were fully prevented by treatment with IMD-0354. Histopathological examination showed that treatment with IMD-0354 protected the lungs from OVA-induced allergic airway inflammation. Our results indicate that IMD-0354 exerts anti-asthmatic action, at least partially, by blocking the activation and clonal expansion of CD4(+) Teff cells in the MLNs, which, consequently, prevents infiltration of the lungs with activated CD4(+) Teff cells. The beneficial effects of IMD-0354 in a mouse model of asthma are not mediated through increased recruitment of Treg cells into the MLNs and lungs and/or local generation of inducible Treg cells.