Interleukin-33 in pulmonary arterial hypertension: a role in disease pathogenesis?

Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance that leads to right ventricular failure. PAH can be a primary disease (idiopathic, IPAH) or secondary to conditions such as connective tissue disease. Interleukin-33 (IL-33), which is the ligand for the ST2 receptor, is a cytokine that acts as an alarmin. Since PAH is associated with the infiltration of inflammatory cells and increased cytokines, we aimed to investigate the role of IL-33 in PAH. Using an IL-33 ELISA we found that IL-33 is increased in the serum of PAH patients, in particular IPAH [1798 +/-846 pg/ml (n=6) vs. 24 +/- 13 pg/ml (n=6), p<0.01], compared to control subjects. We found that the mRNA expression of IL-33 is increased ~8-fold in peripheral blood mononuclear cells isolated from PAH-patients and PAH-animal models compared to control; Il-33 is up-regulated in the lung of animal models of PAH. Injury of pulmonary artery endothelial cells (PAEC) released IL-33, thus implying that the increased circulating IL-33 with PAH may occur if the membrane integrity of PAEC is compromised. Administration of IL-33 (500 ng/day intracheally for four days) induced pulmonary arterial remodeling in WT and IL-33 KO mice, but not ST2 KO mice. Our data demonstrate that IL-33 is increased in PAH, which via ST2-dependent signaling, contributes to remodeling of the PA and hence the pathophysiology of the disease.