IL-33 signaling occurs through an autocrine loop and is also augmented by Notch

Pulmonary hypertension is a disease with many causes, but no lasting cures. Its defining symptom is the creation of lesions within the pulmonary arteries during advanced stages of this disease. Recently it was discovered that Interleukin-33 (IL-33) was elevated in patients with pulmonary hypertension. Elevated IL-33 levels have been found in other diseases such as asthma, rheumatoid arthritis, and chronic obstructive pulmonary diseases, but the cause of secretion is still unclear. We wanted to see if IL-33 has an autocrine or paracrine function in human pulmonary arterial endothelial cells (hPAECs) by culturing the cells with exogenous IL-33. We also looked at IL-33 signaling function while under the influence of the notch ligand Dll4, which has shown to increase IL-33 expression. We found that Dll4 or IL-33 alone are capable of increasing IL-33 expression, but a combined treatment significantly raises IL-33 and receptor ST2 expression. Next, we wanted find out if it was possible to mimic the current mouse model of hypoxia in human cells. This was achieved by culturing hPAECs in the vegfr2 receptor antagonist SU5416 or vehicle, and comparing cultures incubated in hypoxia or normoxia. We saw a decrease in IL-33 when the cultures were under SU5416/hypoxia, as well as an increase in the soluble receptor sST2. This could be the result of a hierarchy where VEGF is a more powerful controller of IL-33 than Dll4. Overall these studies shed more light on the possible mechanisms of IL-33 signaling